Substituted oxazoles and thiazoles derivatives as hPPARγ and hPPARα activators

ABSTRACT

The present invention discloses compounds of formula (I), and tautomeric forms, pharmaceutically acceptable salts, or solvates thereof. Preferably, the compounds of the invention are dual activators of hPPARγ and hPPAR{acute over (α)}.

This application is filed pursuant to 35 U.S.C. §371 as a United StatesNational Phase Application of International Application No.PCT/EP99/05666 filed Aug. 5, 1999, which claims priority from 9817118.4filed Aug. 7, 1998.

The present invention relates to certain novel compounds, to processesfor their preparation, to pharmaceutical compositions containing themand to their use in medicine. More particularly, it relates to compoundswhich exhibit activation, including dual agonist activity, to peroxisomeproliferator-activated receptors gamma (PPARγ) and alpha (PPARα) therebyenabling them to modulate the blood glucose and lipid levels in mammals.

Treatment of type 2 diabetes mellitus usually begins with a combinationof diet and exercise, with progression to oral hypoglycaemics (e.g.sulfonylureas) and in more severe cases, insulin. In the last decade aclass of compounds known as thiazolidinediones (e.g. U.S. Pat. Nos.5,089,514, 4,342,771, 4,367,234, 4,340,605, 5,306,726) have emerged aseffective antidiabetic agents that enhance the insulin sensitivity oftarget tissues (skeletal muscle, liver, adipose) in animal models oftype 2 diabetes mellitus and also reduce lipid and insulin levels inthese animal models.

It has been reported that thiazolidinediones are potent and selectiveactivators of PPARγ and bind directly to the PPARγ receptor (J. M.Lehmann et. al., J. Biol. Chem. 12953-12956, 270 (1995)), providingevidence that PPARγ is a possible target for the therapeutic actions ofthe thiazolidinediones.

PCT patent publication WO 97/31907 discloses certain novel compoundsthat bind to and activate PPARγ. These compounds are indicated to beuseful for the treatment of type 2 diabetes mellitus and other diseases.

Activators of the nuclear receptor PPARγ, for example troglitazone, havebeen shown in the clinic to enhance insulin-action, reduce serum glucoseand have small but significant effects on reducing serum triglyceridelevels in patients with Type 2 diabetes. See, for example, D. E. Kellyet al., Curr. Opin. Endocrinol. Diabetes, 90-96, 5 (2), (1998); M. D.Johnson et al., Ann. Pharmacother., 337-348, 32 (3), (1997); and M.Leutenegger et al., Curr. Ther. Res., 403-416, 58 (7), (1997).

The mechanism for this triglyceride lowering effect appears to bepredominantly increased clearance of very low density lipoproteins(VLDL) through induction of liporotein lipase (LPL) gene expression.See, for. example, B. Staels et al., Arterioscler. Thromb., Vasc. Biol.,1756-1764, 17 (9), (1997).

Fibrates are a class of drugs which may lower serum triglycerides20-50%, lower LDLc 10-15%, shift the LDL particle size from the moreatherogenic small dense to normal dense LDL, and increase HDLc 10-15%.Experimental evidence indicates that the effects of fibrates on serumlipids are mediated through activation of PPARα. See, for example, B.Staels et al., Curr. Pharm. Des., 1-14, 3 (1), (1997). Activation ofPPARα results in transcription of enzymes that increase fatty acidcatabolism and decrease de-novo fatty acid synthesis in the liverresulting in decreased triglyceride synthesis and VLDLproduction/secretion. In addition, PPARα activation decreases productionof apoC-III. Reduction in apoC-III, an inhibitor of LPL activity,increases clearance of VLDL. See, for example, J. Auwerx et al.,Atherosclerosis, (Shannon, Irel.), S29-S37, 124 (Suppl), (1996).

In addition, a dual agonist of PPARα and PPARγ could be effective inreducing the dyslipidemia and hyperinsulinemia associated with impairedglucose tolerance (IGT) or metabolic syndrome and could be effective inpatients with mixed hyperlipidemia. See, for example, U.S. Pat. Nos.5,478,852.

PCT patent publication WO 98/05331 (Paterniti et al.) relates to methodsfor treating diabetes and cardiovascular disease using a PPARγ agonistin combination with a PPARα agonist, or a compound that activates bothPPARγ and PPARα.

BRIEF DESCRIPTION

Briefly, in one aspect, the present invention provides compounds offormula (I), and tautomeric forms, pharmaceutically acceptable salts andsolvates thereof,

wherein;

R¹ is hydrogen or C₁₋₃alkyl;

R² is hydrogen, or C₁₋₈alkyl optionally substituted by one or morehalogens;

R³ is C₁₋₆alkyl, C₄₋₇cycloalkyl or cycloalkenyl, —OC₁₋₆alkyl, —NR′R′(where each R′ is independently hydrogen or C₁₋₃alkyl), a 5 or 6membered heterocyclic group containing at least one oxygen, nitrogen, orsulfur ring atom (optionally substituted by one or more halogen,C₁₋₆alkyl optionally substituted by one or more halogens, —OC₁₋₆alkyloptionally substituted by one or more halogens, —CN, or —NO₂), or phenyl(optionally substituted by one or more halogen, C₁₋₆alkyl optionallysubstituted by one or more halogens, —OC₁₋₆alkyl optionally substitutedby one or more halogens, —CN, or —NO₂);

R⁴ is a 5 or 6 membered heterocyclic group containing at least oneoxygen, nitrogen, or sulfur ring atom (optionally substituted by one ormore halogen, C₁₋₆alkyl optionally substituted by one or more halogens,—OC₁₋₆alkyl optionally substituted by one or more halogens, —CN, or—NO₂), or phenyl (optionally substituted by one or more halogen,C₁₋₆alkyl optionally substituted by one or more halogens, —OC₁₋₆alkyloptionally substituted by one or more halogens, —NR′R′ (as definedabove), —CN, or —NO₂);

R⁵ is hydrogen, halogen, or C₁₋₃alkyl optionally substituted by one ormore halogens;

R⁶ is hydrogen or C₁₋₃alkyl;

X is O or S; and

n is 1, 2, or 3.

Preferably, the compounds of this invention activate both the hPPARγ andhPPARα receptors.

In another aspect, the present invention provides pharmaceuticalcompositions comprising a compound of the invention. As used herein, “acompound of the invention” means a compound of formula (I) or atautomeric form, pharmaceutically acceptable salt, or solvates thereof.

The invention further provides a compound of the invention for use intherapy, and in particular, in human medicine.

In another aspect, the present invention provides a method for treatmentor prevention of a hPPARγ and/or hPPARα mediated disease, risk factor,or condition, comprising administration of a therapeutically effectiveamount of a compound of this invention.

According to another aspect, the present invention provides the use of acompound of the invention for the manufacture of a medicament for the istreatment or prevention of a hPPARγ and/or hPPARα mediated disease.

hPPARγ and/or hPPARα mediated diseases, risk factors, or conditionsinclude hyperglycemia, dyslipidemia, type II diabetes mellitus includingassociated diabetic dyslipidemia, type I diabetes, hypertriglyceridemia,syndrome X, insulin resistance, heart failure, hyperlipidemia,hypercholesteremia, hypertension, cardiovascular disease, includingatherosclerosis, regulation of appetite and food intake in subjectssuffering from disorders such as obesity, anorexia bulimia, and anorexianervosa. In particular, the compounds of the present invention areuseful in the treatment or prevention of hyperglycaemia, dyslipidemia,and type II diabetes mellitus including associated diabeticdyslipidemia.

DETAILED DESCRIPTION

Preferably, R¹ is hydrogen or methyl. Most preferably, R¹ is hydrogen.

Preferably, R² is C₁₋₈alkyl optionally substituted by one or morehalogens. Preferably, said halogen is fluorine. Most preferably, R² isstraight-chain.

Preferably, R³ is pyridine, pyrazine, thiophene, furan, thiazole, orphenyl (any of which may be optionally substituted by one or morehalogen, C₁₋₆alkyl optionally substituted by one or more halogens,—OC₁₋₆alkyl optionally substituted by one or more halogens, —CN, or—NO₂), or C₄₋₇cycloalkyl. Most preferably, R³ is phenyl (optionallysubstituted by one or more halogen, C₁₋₆alkyl optionally substituted byone or more halogens, —OC₁₋₆alkyl optionally substituted by one or morehalogens, —CN, or —NO₂).

Preferably R⁴ is phenyl (optionally substituted by one or more halogen,C₁₋₆alkyl optionally substituted by one or more halogens, or —OC₁₋₆alkyloptionally substituted by one or more halogens). Preferably, saidhalogen is fluorine. Most preferably R⁴ is phenyl either unsubstitutedor substituted with 1, 2, or 3 fluorine atoms.

Preferably, R⁵ is hydrogen, halogen, or C₁₋₃alkyl optionally substitutedby one or more halogens. Most preferably R⁵ is hydrogen.

Preferably R⁶ is methyl or ethyl.

Preferably n is 2.

Preferably, the carbon atom bonded to CO₂R¹ is in the S configuration.In other words, preferably, the absolute configuration around thatcarbon is:

Suitable compounds of the present invention include:

(2S)-2-{[(Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

(2S)-3-(4-{2-[2-(4-fluorophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoicacid

(2S)-3-(4-{2-[2-(4-isopropoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoicacid

(2S)-3-(4-{2-[2-(4-methoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoicacid

(2S)-2-{[(Z)-1-ethyl-3-oxo-3-phenyl-1-propenyl]amino}-3-[4-(2-{5-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}ethoxy)phenyl]propanoic acid

(2S)-2-{[(Z)-1-ethyl-3-(4-fluorophenyl)-3-oxo-1-propenyl]amino}-3-(4-{2-[2-(4-methoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)propanoicacid

(2S)-2-{[(Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]amino}-3-[4-(2-{5-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}ethoxy)phenyl]propanoicacid

(2S)-2-{[(Z)-1-ethyl-3-oxo-3-phenyl-1-propenyl]amino}-3-(4-{2-[2-(4-fluorophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)propanoicacid

(2S)-2-{[(Z)-1-ethyl-3-(4-fluorophenyl)-3-oxo-1-propenyl]amino}-3-(4-{2-[2-(4-fluorophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)propanoicacid

(2S)-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-{4-[2-(5-methyl-2-phenyl-1,3-thiazol-4-yl)ethoxy]phenyl}propanoicacid

(2S)-2-{[(Z)-3-(4-fluorophenyl)-1-methyl-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

(2S)-2-{[(Z)-1-methyl-3-oxo-3-(2,3,4-trifluorophenyl)-1-propenyl]amino}-3-{4-[2-(5methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

(2S)-2-{[(Z)-1-methyl-3-(4-nitrophenyl)-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

(2S)-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

(2S)-2-{[(Z)-1-ethyl-3-(4-fluorophenyl)-3-oxo-1-propenyl]amino}-3-(4-{2-[2-(4-isopropoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)propanoicacid

(2S)-2-{[(Z)-1-methyl-3-oxo-3-(2,4,5-trifluorophenyl)-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

(2S)-2-{[(Z)-1-ethyl-3-oxo-3-phenyl-1-propenyl]amino}-3-(4-{2-[2-(4-isopropoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)propanoicacid

(2S)-2-{(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-{4-([2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

(2S)-2-{[(Z)-1-methyl-3-(4-methylphenyl)-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

(2S)-2-{[(Z)-1-ethyl-3-oxo-3-phenyl-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

(2S)-3-(4-{2-[2-(4-fluorophenyl)-5-methyl-1,3-thiazol-4-yl]ethoxy}phenyl)-2-({[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoicacid

(2S)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-(4-{2-[2-(4-fluorophenyl)-5-methyl-1,3-thiazol-4-yl]ethoxy}phenyl)propanoicacid

(2S)-2-{[(Z)-1-butyl-3-oxo-3-phenyl-1-propenyl]amino}-3-{4-[2-(5methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

(2S)-2-{[(Z)-3-(4-chlorophenyl)-1-methyl-3-oxo-1-propenyl]amino{-3-4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

(2S)-2-{[(Z)-1-methyl-3-(3-nitrophenyl-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

(2S)-2-({(Z)-3-[2-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-3-oxo-1-propenyl}amino)-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

(2S)-2-{[(Z)-3-(4-isopropoxyphenyl)-1-methyl-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

(2S)-2-{[(Z)-3-(2-chlorophenylyl)-1-methyl-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

(2S)-2-{[(Z)-3-(2-furyl)-1-methyl-3-oxo-1-propenylamino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

(2S)-2-{[(Z)-1-methyl-3-oxo-3-(2-pyrazinyl)-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

(2S)-2-{[(Z)-3-(2,4-difluorophenyl)-1-methyl-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

(2S)-2-{[(Z)-1-methyl-3-oxo-3-(1,3-thiazol-2-yl)-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

(2S)-2-{[(Z)-1-methyl-3-oxo-3-(3-thienyl)-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

(2S)-2-{[(Z)-1-methyl-3-oxo-3-(2-pyridinyl)-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

(2S)-2-{[(Z)-1-ethyl-3-(4-fluorophenyl)-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

(2S)-2-{[(Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-thiazol-4-yl)ethoxy]phenyl}propanoicacid

(2S)-2-{[(Z)-3-(2-fluorophenyl)-1-methyl-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

(2S)-2-{[(Z)-3-(2,3-difluorophenyl)-1-methyl-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

(2S)-2-{[(Z)-3-(2-hydroxyphenyl-1-methyl-3-oxo-1-propenyl]amino}-3-{4-[2-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

(2S)-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}-2-{[(Z)-3-oxo-3-phenyl-1-propyl-1-propenyl]amino}propanoicacid

(2S)-2-{[(Z)-3-(4-methoxyphenyl)-1-methyl-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

(2S)-3-(4-{2-[2-(4-methoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)-2-{[(Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]amino}propanoicacid

(2S)-2-{[(Z)-3-cyclohexyl-1-methyl-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

(2S)-3-(4-{2-[2-(4-isopropoxyphenyl)-5methyl-1,3-oxazol-4-yl]ethoxy}phenyl)-2-{[(Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]amino}propanoicacid

(2S)-2-{[(Z)-1-heptyl-3-oxo-3-phenyl-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

(2S)-2-{[(Z)-1-methyl-3-(3-methylphenyl)-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

(2S)-2-{[(Z)-1-ethyl-3-oxo-3-phenyl-1-propenyl]amino}-3-(4-{2-[2-(4-methoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)propanoic acid

(2S)-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}-2-{-[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoicacid

(2S)-3-{4-[2-(5-methyl-2-phenyl-1,3-thiazol-4-yl)ethoxy]phenyl}-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoicacid

(2S)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-(4-{2-[2-(4-fluorophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)propanoicacid

(2S)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-(4-{2-[2-(4-isopropoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)propanoicacid

(2S)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-(4-{2-[2-(4-methoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)propanoicacid

(2S)-3-(4-{2-[2-(4-fluorophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoicacid

(2S)-2-{[(Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]amino}-3-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenyl}propanoicacid

(2S)-3-{4-[2-(5-ethyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}-2-{[(Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]amino}propanoicacid

(2S)-2-{[(Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]amino}-3-{4-[2-(2-phenyl-5-propyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

(2S)-2-{[(Z)-1-methyl-3oxo-3-phenyl-1-propenyl]amino}-3-{4-[3-(5-methyl-2-phenyl-1,3-oxazol-4-yl)propoxy]phenyl}propanoicacid

(2S)-3-{4-[2-(5-ethyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoicacid

(2S)-3-{4-[3-(5-methyl-2-phenyl-1,3-oxazol-4-yl)propoxy]phenyl}-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoicacid

(2S)-3-{4-[(2-(5-ethyl-2-phenyl-1,3-thiazol-4-yl)ethoxy]phenyl}-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoicacid

(2S)-3-(4-{2-[5-ethyl-2-(4-fluorophenyl)-1,3-oxazol-4yl]ethoxy}phenyl)-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoicacid

(2S)-3-(4-{3-[5-ethyl-2-(4-fluorophenyl)-1,3-oxazol-4-yl]propoxy}phenyl)-2-{[(Z)-3oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoicacid

(2S)-3-(4-{2-[5-ethyl-2-(4-fluorophenyl)-1,3-thiazol-4-yl]ethoxy}phenyl)-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoicacid

(2S)-3-(4-{3-[5-ethyl-2-(4-fluorophenyl)-1,3-oxazol-4-yl]propoxy}phenyl)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoicacid

(2S)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-{4-[3-(5-ethyl-2-phenyl-1,3-oxazol-4-yl)propoxy]phenyl}propanoicacid

(2S)-3-(4-{3-[5-ethyl-2-(4-fluorophenyl)-1,3-oxazol-4-yl]propoxy}phenyl)-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoicacid

(2S)-3-{4-[3-(5-ethyl-2-phenyl-1,3-oxazol-4-yl)propoxy]phenyl}-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoicacid

(2S)-3-{4-[3-(5-ethyl-2-phenyl-1,3-oxazol-4-yl)propoxy]phenyl}-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoicacid

(2S)-3-{4-[(5-ethyl-2-phenyl-1,3-thiazol-4-yl)methoxy]phenyl}-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoicacid

(2S)-3-{4-[(5-ethyl-2-phenyl-1,3-thiazol-4-yl)methoxy]phenyl}-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoicacid

(2S)-3-{4-[(5-ethyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenyl}-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoicacid

(2S)-3-(4-{[5-ethyl-2-(4-fluorophenyl)-1,3-oxazol-4-yl]methoxy}phenyl)-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoicacid

(2S)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-{4-[(5ethyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenyl}propanoicacid

(2S)-3-(4-{[5-ethyl-2-(4-fluorophenyl)-1,3-oxazol-4-yl]methoxy}phenyl)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoicacid

(2S)-3-{4-[(5-ethyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenyl}-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoicacid

(2S)-3-(4-{[5ethyl-2-(4-fluorophenyl)-1,3-oxazol-4-yl]methoxy}phenyl)-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoicacid

(2S)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-{4-[(5ethyl-2-phenyl-1,3-thiazol-4-yl)methoxy]phenyl}propanoicacid

(2S)-3-(4-{2-[5-ethyl-2-(4-fluorophenyl)-1,3-oxazol-4-yl]ethoxy}phenyl)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoicacid

(2S)-3-(4-{2-[5-ethyl-2-(4-fluorophenyl)-1,3-thiazol-4-yl]ethoxy}phenyl)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoicacid

(2S)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-{4-[2-(5-ethyl-2-phenyl-1,3-thiazol-4-yl)ethoxy]phenyl}propanoicacid, and pharmaceutically acceptable salts and solvates thereof.

Preferred compounds of the invention include

(2S)-2-{[(Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

(2S)-2-{[(Z)-1-ethyl-3-oxo-3-phenyl-1-propenyl]amino}-3-[4-(2-{5-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}ethoxy)phenyl]propanoicacid

(2S)-2-{[(Z)-1-methyl-3-oxo-3-(2,3,4-trifluorophenyl)-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

(2S)-2-{[(Z)-1-methyl-3-(4-nitrophenyl)-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

(2S)-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

(2S)-2-{[(Z)-1-methyl-3-oxo-3-(2,4,5-trifluorophenyl)-1-propenyl]amino}-3-4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

(2S)-2-{[(Z)-1-ethyl-3-oxo-3-phenyl-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

(2S)-3-(4-{2-[2-(4-fluorophenyl)-5-methyl-1,3-thiazol-4-yl]ethoxy}phenyl)-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoicacid

(2S)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-(4-{2-[2-(4-fluorophenyl-5-methyl-1,3-thiazol-4-yl]ethoxy}phenyl)propanoicacid

(2S)-2-{[(Z)-1-butyl-3-oxo-3-phenyl-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

(2S)-2-{[(Z)-3-(4-chlorophenyl)-1-methyl-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

(2S)-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}-2-{[(Z)-3-oxo-3-phenyl-1-propyl-1-propenyl]amino}propanoicacid

(2S)-3-{4-[2-(5methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoicacid

(2S)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-(4-{2-[2-(4-fluorophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)propanoicacid

(2S)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-(4-{2-[2-(4-methoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)propanoicacid

(2S)-3-(4-{2-[2-(4-fluorophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)-2-{[(Z3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoicacid

(2S)-2-{[(Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]amino}-3-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenyl}propanoicacid

(2S)-3-{4-[2-(5-ethyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}-2-{[(Z)-3-oxo-3-phenyl-1-propenyl]amino}propanoicacid

(2S)-2-{[(Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]amino{-3-4-[3-(5-methyl-2-phenyl-1,3-oxazol-4-yl)propoxy]phenyl}propanoicacid

(2S)-3-{4-[2-(5-ethyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl)-2-{[(Z)-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoicacid

(2S)-3-{4-[2-(5ethyl-2-phenyl-1,3-thiazol-4-yl)ethoxy]phenyl}-2[(Z)-3-oxo-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoicacid

(2S)-3-(4-{2-[5-ethyl-2-(4-fluorophenyl)-1,3-oxazol-4-yl]ethoxy}phenyl)-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoicacid

(2S)-3-(4-{3-[5-ethyl-2-(4-fluorophenyl)-1,3-oxazol-4-yl]propoxy)}phenyl)-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoicacid

(2S)-3-(4-{2-[5-ethyl-2-(4-fluorophenyl)-1,3-thiazol-4-yl]ethoxy}phenyl)-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)1-propenyl]amino}propanoicacid

(2S)-3-(4-{[5-ethyl-2-(4-fluorophenyl)-1,3-oxazol-4-yl]propoxy}phenyl)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoicacid

(2S)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-{4-[3-(5-ethyl-2-phenyl-1,3-oxazol-4-yl)propoxy]phenyl}propanoicacid

(2S)-3-(4-{3-[5-ethyl-2-4-fluorophenyl)-1,3-oxazol-4-yl]propoxy}phenyl)-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoicacid

(2S)-3-{4-[3-(5-ethyl-2-phenyl-1,3-oxazol-4-y)propoxy]pheny}-l2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoicacid

(2S)-3-(4-{[5ethyl-2-(4-fluorophenyl)-1,3-oxazol-4-yl]methoxy}phenyl)-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoicacid

(2S)-3-{4-[(5-ethyl-2-phenyl-1,3-oxazol-4-yL)methoxy]phenyl}-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoicacid

(2S)-3-(4-{[5-ethyl-2-(4-fluorophenyl)-1,3-oxazol-4-yl]methoxy}phenyl)-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoicacid

(2S)-3-(4-{2-[5-ethyl-2-(4-fluorophenyl)-1,3-thiazol-4-yl]ethoxy}phenyl)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoicacid and pharmaceutically acceptable salts and solvates thereof.

Many of the compounds of formula (I) are dual activators of hPPARγ andhPPARα As used herein, by “activating compound”, or “activator”, or thelike, is meant those compounds which achieve at least 50% activation ofhuman PPARγ (“hPPARγ”) or hPPARα (relative to the appropriate indicatedpositive control) in the transfection assay described below atconcentrations of 10⁻⁷ M or less. As used herein, a “dual activator” isa compound that is an activator of both PPARγ and PPARα.${The}\quad {ratio}\quad \frac{{EC}_{50}\quad {hPPAR}\quad \alpha}{{EC}_{50}\quad {hPPAR}\quad \gamma}$

defines the relative activity of hPPARα to hPPARγ. Preferably, the dualactivators of this invention have a relative hPPARα to hPPARγ activityof from 0.02 to 50.

Those skilled in the art will recognize that stereocenters exist incompounds of formula (I). Accordingly, the present invention includesall possible stereoisomers and geometric isomers of formula (I) andincludes not only racemic compounds but also the optically activeisomers as well. When a compound of formula (I) is desired as a singleenantiomer, it may be obtained either by resolution of the final productor by stereospecific synthesis from either isomerically pure startingmaterial or any convenient intermediate. Resolution of the finalproduct, an intermediate or a starting material may be effected by anysuitable method known in the art. See, for example, Stereochemistry ofCarbon Compounds by E. L. Eliel (Mcgraw Hill, 1962) and Tables ofResolving Agents by S. H. Wilen. Additionally, in situations wheretautomers of the compounds of formula (I) are possible, the presentinvention is intended to include all tautomeric forms of the compounds.

It will also be appreciated by those skilled in the art that thecompounds of the present invention may also be utilized in the form of apharmaceutically acceptable salt or solvate thereof. The physiologicallyacceptable salts of the compounds of formula (I) include conventionalsalts formed from pharmaceutically acceptable inorganic or organic acidsor bases as well as quaternary ammonium acid addition salts. Morespecific examples of suitable s acid salts include hydrochloric,hydrobromic, sulfuric, phosphoric, nitric, perchloric, fumaric, acetic,propionic, succinic, glycolic, formic, lactic, maleic, tartaric, citric,pamoic, malonic, hydroxymaleic, phenylacetic, glutamic, benzoic,salicylic, fumaric, toluenesulfonic, methanesulfonic,naphthalene-2-sulfonic, benzenesulfonic hydroxynaphthoic, hydroiodic,malic, steroic, tannic and the like. Other acids such as oxalic, whilenot in themselves pharmaceutically acceptable, may be useful in thepreparation of salts useful as intermediates in obtaining the compoundsof the invention and their pharmaceutically acceptable salts. Morespecific examples of suitable basic salts include sodium, lithium,potassium, magnesium, aluminium, calcium, zinc,N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, N-methylglucamine and procaine salts. Referenceshereinafter to a compound according to the invention include bothcompounds of formula (I) and their pharmaceutically acceptable salts andsolvates.

The terms C₁₋₃alkyl, C₄₋₆cycloalkyl, C₁alkylene, C₂₋₆alkenyl and thelike, as used herein, indicate groups that may contain the indicatedrange of carbon atoms, for example 1 to 3 carbon atoms. Unless otherwiseindicated, such groups can be straight chained or branched.

The term 5- or 6-membered heterocyclic group as used herein includes 5-or 6-membered substituted or unsubstituted heterocycloalkyl andheteroaryl groups, e.g. substituted or unsubstituted imidazolidinyl,piperidyl, piperazinyl pyrrolidinyl, morpholinyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, pyranyl, furyl,thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl,triazolyl or tetrazolyl. Particularly preferred heterocycles arepyridine, pyrazine, thiophene, furan, and thiazole.

It will be appreciated by those skilled in the art that reference hereinto treatment extends to prophylaxis as well as the treatment ofestablished diseases or symptoms. Moreover, it will be appreciated thatthe amount of a compound of the invention required for use in treatmentwill vary with the nature of the condition being treated and the age andthe condition of the patient and will be ultimately at the discretion ofthe attendant physician or veterinarian. In general, however, dosesemployed for adult human treatment will typically be in the range of0.02-5000 mg per day, preferably 1-1500 mg per day. The desired dose mayconveniently be presented in a single dose or as divided dosesadministered at appropriate intervals, for example as two, three, fouror more sub-doses per day.

While it is possible that compounds of the present invention may betherapeutically administered as the raw chemical, it is preferable topresent the active ingredient as a pharmaceutical formulation.Accordingly, the present invention further provides for a pharmaceuticalformulation comprising a compound of formula (I) or a pharmaceuticallyacceptable salt or solvate thereof together with one or morepharmaceutically acceptable carriers therefor and, optionally, othertherapeutic and/or prophylactic ingredients.

Formulations of the present invention include those especiallyformulated for oral, buccal, parenteral, transdermal, inhalation,intranasal, transmucosal, implant, or rectal administration, however,oral administration is preferred. For buccal administration, theformulation may take the form of tablets or lozenges formulated inconventional manner. Tablets and capsules for oral administration maycontain conventional excipients such as binding agents, (for example,syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch orpolyvinylpyrrolidone), fillers (for example, lactose, sugar,microcrystalline cellulose, maize-starch, calcium phosphate orsorbitol), lubricants (for example, magnesium stearate, stearic acid,talc, polyethylene glycol or silica), disintegrants (for example, potatostarch or sodium starch glycollate) or wetting agents, such as sodiumlauryl sulfate. The tablets may be coated according to methodswell-known in the art.

Alternatively, the compounds of the present invention may beincorporated into oral liquid preparations such as aqueous or oilysuspensions, solutions, emulsions, syrups or elixirs, for example.Moreover, formulations containing these compounds may be presented as adry product for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may contain conventional additives such assuspending agents such as sorbitol syrup, methyl cellulose,glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fats;emulsifying agents such as lecithin, sorbitan mono-oleate or acacia;non-aqueous vehicles (which may include edible oils) such as almond oil,fractionated coconut oil, oily esters, propylene glycol or ethylalcohol; and preservatives such as methyl or propyl p-hydroxybenzoatesor sorbic acid. Such preparations may also be formulated assuppositories, e.g., containing conventional suppository bases such ascocoa butter or other glycerides.

Additionally, formulations of the present invention may be formulatedfor parenteral administration by injection or continuous infusion.Formulations for injection may take such forms as suspensions,solutions, or emulsions in oily or aqueous vehicles, and may containformulatory agents such as suspending, stabilizing and/or dispersingagents. Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle (e.g., sterile, pyrogen-free water)before use.

The formulations according to the invention may also be formulated as adepot preparation. Such long acting formulations may be administered byimplantation (for example, subcutaneously or intramuscularly) or byintramuscular injection. Accordingly, the compounds of the invention maybe formulated with suitable polymeric or hydrophobic materials (as anemulsion in an acceptable oil, for example), ion exchange resins or assparingly soluble derivatives as a sparingly soluble salt, for example.

The formulations according to the invention may contain between 0.1-99%of the active ingredient, conveniently from 30-95% for tablets andcapsules and 3-50% for liquid preparations.

There is further provided by the present invention processes for thepreparation of compounds of the invention Unless otherwise indicated,R′, R¹, R², R³, R⁴, R⁵, R⁶, n, and X are as defined above.

A compound of structural formula (I) may be prepared from thecondensation of a compound of formula (II):

with a compound of formula (III), for example, in a polar organicsolvent, such,

as methanol, at temperatures from −20° C. to 150° C., such as 65° C., inthe presence of a dehydrating agent such as trimethylorthoformate and/ormolecular sieves.

Alternatively, a compound of formula (I) where R⁵ is hydrogen may beprepared by reaction of a compound of formula (II) with a compound of:

formula (IVa) in an organic solvent such as methanol at temperaturesfrom −20° C. to 150° C., such as 65° C., in the presence of a base, suchas diisopropylethylamine.

Compounds of Formula (I) where R² is CF₃ may be prepared from thereaction of compounds of formula (II) with compounds of formula (IVb) inan organic solvent such as methanol at temperatures from −20° C. to 150°C., such as 23° C., in the presence of a base such as diisopropylamine.

Compounds of formula (II) may be prepared via alkylation of compounds offormula (V), preferably where R¹ is hydrogen, with compounds of formula(VI), where R″ is an activating group such as mesylate followed by:

deprotection of the amine under acidic conditions such as 4.0 N HCl indioxane solution at 20° C., or trifluoroacetic acid in dichloromethaneat 20° C.

Alternatively, compounds of formula (II) may be prepared from reactionof compounds of formula (V), preferably where R¹ is methyl, withcompounds of formula (VI), preferably where R″ is hydrogen, in anorganic solvent such as toluene at temperatures from −20° C. to 150° C.such as 20° C. in the presence of triphenylphosphine anddiethylazodicarboxylate in a Mitsunobu type procedure. Standard methylester hydrolysis conditions such as lithium hydroxide in tetrahydrofuranand water at 20° C. followed by amine deprotection as hereinbeforedescribed (see also Greene, T. W. and Wutz, P. G. M. “Protective Groupsin Organic Synthesis” 2^(nd) edition, 1991, John Wiley and Sons for ageneral discussion on protective group installation/removal) providescompounds of structural formula (II).

Compounds of formula (V) are commercially available and may also beprepared by someone skilled in the art from commercially availablecompounds.

Compounds of formula (VI), for example where R″ is mesylate, may beprepared by reaction of an alcohol of formula (VI) where R″ is hydrogen,with methanesulfonyl chloride in an organic solvent such astetrahydrofuran at temperatures from −20° C. to 150° C. such as 0° C. inthe presence of an amine base such as triethylamine.

Alcohols of formula (VI) where R″ is hydrogen, may be prepared viareduction of the corresponding carboxylic acid or ester of formula (IX)in an organic solvent such as diethyl ether at temperatures of from −20°C. to 100° C., such as 0° C., in the presence of a metal hydride reagentsuch as lithium aluminum hydride. These acids or esters of formula (IX)may be prepared by a two stage alkylation/cyclization process between anamide or thioamide compound of formula (VII), and a bromoketoestercompound of formula (VII), where R′″ is alkyl. Thealkylation/cyclization reaction may be performed in an organic solventsuch as toluene or ethanol at temperatures of from −20° C. to 200° C.,such as 110° C., in the presence of a base such as triethylamine. Forthe preparation of (VIII), see: Chem. Pharm. Bull. (1986), 34(7),2840-51, J. Med. Chem. (1992), 35(14), 2617-26, patent WO 9731907.

Amides or thioamides of formula (VII) are commercially available or maybe prepared from readily available compounds by one skilled in the art.

Compounds of formula (III) are commercially available or may be readilyprepared by one skilled in the art, for example, by reacting a ketone offormula (X) with an ester of formula (XII), or by reacting a ketone offormula (XIII) with an ester of formula (XI), by reaction in an organicsolvent, such as tetrahydrofuran, at temperatures from −20° C. to 150°C., such as 20° C., in the presence of a base, such as sodium hydride, ametal cation scavenger, such as dibenzo-18-crown-6, and catalyticquantities of an alcohol, such as ethanol (See: Popic, V. V. et al.Synthesis 1991, 195-197).

Compounds of formula (IVa) may be prepared from the addition ofcompounds of formula (XV) to compounds of formula (XIV) in an organicsolvent such as tetrahydofuran at temperatures of from −100° C. to 100 °C. such as −78 ° C. followed by oxidation of the intermediatepropargyllic alcohol with an oxidant, such as manganese dioxide, in anorganic solvent, such as dichloromethane, at temperatures from −20° C.to 100° C., such as 20° C.

Alternatively, certain yne-one compounds of formula (IVa) may beprepared by dehydration of a compound of formula (III) where R⁵ ishydrogen in an organic solvent, such as dichloromethane, at temperaturesfrom −20° C. to 100° C., such as 20° C., in the presence oftriphenylphosphine, bromine, and a base, such as triethylamine. When R²is CF₃, R⁵ is hydrogen, and R³ is phenyl, a compound of formula (III) inan organic solvent, such as dichloromethane, at temperatures from −20°C. to 100° C., such as 20° C., in is the presence of triphenylphosphine,bromine, and a base, such as triethylamine yields a compound of formula(IVb). Compounds of formula (X), (XI), (XII), (XIII), (XIV), and (XV)are commercially available or may be prepared from readily availablematerials from one skilled in the art.

Suitable reaction conditions are described below and in the accompanyingExamples. See also, for example, Chung et al., SelectiveFunctionalization of (S)Tyrosine, Tetrahedron, 49(26), pp. 5767-5776,(1993), Solar et al., Selective O-Alkylation of Tyrosine, Journal ofOrganic Chemistry, 31, pp 1996-1997 (1966), O. Mitsunobu, Synthesis, p 1(1981), and D. L. Hughes, Org. React. Vol. 42, p 335 (1992).

A compound of formula (I) can be converted to another compound offormula (I). A particular interconversion reaction involves conversionof a compound of formula (I) wherein R′ represents C₁₋₃alkyl, to acompound of formula (I) wherein R′ represents hydrogen, suitablyemploying hydrolytic techniques e.g. an alkali metal hydroxide, in thepresence of an ether solvent e.g. tetrahydrofuran and an alcoholicsolvent e.g. methanol or the like. It will therefore be appreciated bypersons skilled in the art that compounds which fall within generalformula (I), may in some instances, be hereinafter described in theintermediate section, as they are useful for the preparation of othercompounds of formula (I).

For any of the general processes and schemes described above, it may benecessary and/or desirable to protect sensitive or reactive groups.Protecting groups are employed according to standard methods of organicsynthesis (T. W. Green and P. G. M. Wuts (1991) Protecting Groups inOrganic Synthesis, John Wiley & Sons). These groups are removed at aconvenient stage of synthesis using methods known from the art. Thus,for example, amino groups may be protected by a group selected fromaralkyl (e.g. benzyl), acyl, or sulfonyl, e.g. allylsulfonyl,tert-butoxycarbonyl, phthalimide, or tosyl; subsequent removal of theprotecting group being effected when desired by hydrolysis orhydrogenolysis as appropriate using standard conditions. Thus, forexample, tert-butoxycarbonyl groups may be removed by hydrolysis underacidic conditions. Hydroxyl and carboxyl groups may be protected usingany conventional hydroxyl or carboxyl protecting group. Examples ofsuitable hydroxyl and carboxyl protecting groups include groups selectedfrom alkyl, e.g. methyl, tert-butyl, or methoxymethyl, aralkyl, e.g.benzyl, diphenylmethyl, or triphenylmethyl, heterocyclic groups such astetrahydropyranyl, acyl. e.g. acetyl or benzoyl, and silyl groups suchas trialkylsilyl, e.g. tert-butyldimethylsilyl. The hydroxyl protectinggroups may be removed by conventional techniques. Thus, for example,alkyl, silyl, acyl, and heterocyclic groups may be removed by hydrolysisunder acidic or basic conditions. Aralkyl groups such as triphenylmethylmay similarly be removed by hydrolysis under acidic conditions. Aralkylgroups such as benzyl may be cleaved by hydrogenolysis in the presenceof a Noble metal catalyst such as palladium-on-charcoal. Silyl groupsmay also conveniently be removed using a source of fluoride ions such astetra-n-butylammonium fluoride.

The following examples are set forth to illustrate the synthesis of someparticular compounds of the present invention and to further exemplifyparticular applications of general processes described above.Accordingly, the following Example section is in no way intended tolimit the scope of the invention contemplated herein.

EXAMPLES

As used herein the symbols and conventions used in these processes,schemes and examples are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety. Unless otherwise noted, all starting materials were obtainedfrom commercial suppliers and used without further purification.Specifically, the following abbreviations may be used in the examplesand throughout the specification: g (grams); mg (milligrams); L(liters); mL (milliliters); μL (microliters); N (normal); mM(millimolar); mmol (millimoles); i. v. (intravenous); Hz (Hertz); MHz(megahertz); mol (moles); RT or rt (room temperature); min (minutes); h(hours); mp. (melting point); TLC (thin layer chromatography); HPLC(high pressure liquid chromatography); ms (mass spectrum);ES+(electrospray); R_(f) (retention fraction); (t_(r) (retention time);RP (reverse phase); MeOH (methanol); TFA (trifluoroacetic acid); HCl(hydrochloric acid); HCO₂H (formic acid); THF (tetrahydrofuran); CH₃CN(acetonitrile); EtOH (ethanol); CDCl₃ (deuterated chloroform); DMSO(dimethylsulfoxide); DMSO-d₆ (dimethylsulfoxide-deuterated); EtOAc(ethyl acetate); DCM or CH₂Cl₂ (dichloromethane); DMF(dimethylformamide); Et3N (triethylamine); MgSO₄ (magnesium sulfate);H₂O (water); LAH (lithium aluminum hydride; NaH (sodium hydride); Na₂CO₃(sodium carbonate); Na₂SO₄ (sodium sulfate); MnO₂ (manganese dioxide);KCN (potassium cyanide); BH₃.THF (borane.tetrahydofuran complex); NaOMe(sodium methoxide); IPA (isoprropanol); Pd/C (palladium on carbon);NaOH(sodium hydroxide; LiOH (lithium hydroxide); DIEA(diisopropylethylamine); Et₂O (diethyl ether; diethyl azodicaboxylate(DEAD); Diisopropyl azodicarboxylate (DIAD); tert-butyloxycarbonyl(BOC); NaHCO₃ (saturated aqueous sodium bicarbonate). Brine refers to asaturated aqueous solution of NaCl. Unless otherwise indicated, alltemperatures are expressed in ° C. (degrees Centigrade). All reactionsconducted at room temperature unless otherwise noted.

The ¹H NMR spectra were recorded on a Varian VXR-300, a VarianUnity-300, or a Varian Unity400 instrument. Chemical shifts areexpressed in parts per million (ppm, δ units). Coupling constants are inunits of hertz (Hz). Splitting patterns are designated as s, singlet; d,doublet; t, triplet; q, quartet; m, multiplet; br, broad; hept,heptuplet.

Low-resolution mass spectra (MS) were recorded on a JOEL JMS-AX505HA,JOEL SX-102, Micromass Platform 2 LC/Ms, or a SCIEX-APliiispectrometers. All mass spectra were taken under electrospray ionization(ES, either in the positive ion mode or negative ion mode) or by fastatom bombardment (FAB) methods. Infrared (IR) spectra were obtained on aNicolet 510 FT-IR spectrometer using a 1-mm NaCl cell. All reactionswere monitored by thin-layer chromatography on 0.25 mm E. Merck silicagel plates (60F-254), visualized with UV light, iodine staining, or 7%ethanolic phosphomolybdic acid or p-anisidehyde solutions. Flash columnchromatography was performed on silica gel (230-400 mesh, Merck).

Analytical purity was assessed on a Hewlett Packard series 1050 or 1100system equipped with a diode array spectrometer. The stationary phasewas either a Dynamax C8 column (25 cm×4.1 mm), a Dynamax 60A C18 column(25 cm×4.6 mm), a Vydac C18 column (5 m, 4.6 mm×250 mm), a Supelco C18column (5m, 4.6 mm×150 mm), or a Rainin C18 column (5 m, 4.6 mm×250 mm).The flow rate was 1.0 to 1.5 ml/min. (t0=2.8 or 3.0 min.) and thesolvent systems were as described below. Enantiomeric purity wasassessed using either a Chiralpak AD column (25 cm×4.6 mm) or aChiralpak OD column (25 cm×4.6 mm) on either a Hewlet Packard series1050 HPLC system equipped with a diode array spectrometer or on aSupercritical Fluid (SFC) system using CO₂/methanol as the mobile phase.

Intermediate 1: 2-[5-methyl-2-phenyl-1,3-oxazol-4-yl]acetic acid methylester

To a solution of 140 g (0.67 mol) of methyl 4-bromo-3-oxo-pentanoate in300 mL of anhydrous toluene was added 210 g (1.73 mol) of benzamide, 132g (0.93 mol) of sodium hydrogen phosphate, and ˜20 mL of EtOH. Thesuspension was stirred with heating to 95° C. for 24 h, then cooled to0° C., filtered, and the solids washed with cyclohexane (2×100 mL)followed by 20% EtOAc in hexanes (200 mL). The combined filtrates werewashed with 2×100 mL 10% KOH solution and brine (100 mL). The organicswere dried (MgSO₄), concentrated to a thin oil, and purified bychromatography on 1 kg of silica gel (230-400 mesh). Gradient elution ofthe column with 10% to 50% EtOAc in Hexanes gave 54 grams (35% yield) ofthe title compound as a pale yellow oil; ¹H NMR (CDCl₃, 400 MHz)δ8.0-7.98 (m, 2H), 7.43-7.40 (m, 3H), 3.73 (s, 3H), 3.59 (s, 2H), 2.37(s, 3H); low resolution MS (ES+)m/e 232.4 (MH⁺); TLC R_(f)=0.64 (4/1hexanes/EtOAc).

Intermediate 1B: 2-[5-ethyl-2-phenyl-1,3oxazol-4-yl]acetic acid ethylester

The title compound was prepared (as described above for the preparationof example 1) from ethyl 4-bromo-3-oxo-hexanoate (3.32 g, 14 mmol) and6.79 g (56 mmol) of benzamide to give 710 mg of Intermediate 1B: TLCR_(f)=0.69 (2/1 hexanes/EtOAc); ¹H NMR (CDCl₃, 300 MHz) δ7.98 (m, 2H),7.41 (m, 3H), 4.18 (q, 2H, J=6.9), 3.57 (s, 2H), 2.72 (q, 2H, J=7.5),1.29-1.24 low resolution MS (ES⁺)m/e 260.1 (MH⁺).

Intermediate 1C: 2-[2-phenyl-5-propyl-1,3-oxazol-4-yl]acetic acid ethylester

The title compound was prepared (as described above for the preparationof example 1) from ethyl 4-bromo-3-oxo-heptanoate (2.83 g, 11.4 mmol)and 5.51 g (45 mmol) of benzamide to give 820 mg of Intermediate IC: TLCR_(f)=0.70 (2/1 hexanes/EtOAc); ¹H NMR (CDCl₃, 300 MHz) δ7.98 (m, 2H),7.43-7.4 (m, 3H), 4.18 (q, 2H, J=7.2), 3.56 (s, 2H), 2.66 (t, 2H,J=7.5), 1.76-1.68 (m, 2H), 1.27 (t, 3H, J=7.2), 0.99 (t, 3H, J=7.2); lowresolution MS (ES⁺)m/e 274.1 (MH⁺).

Intermediate 1D: 5-methyl-2-phenyl-1,3oxazole4carboxylic acid

Commercial sources.

Intermediate 1E: 5ethyl-2-phenyl-1,3-oxazole4-carboxylic acid

Intermediate 1E was prepared (as described below for the preparation ofintermediate 2B) from 4.08 g of benzamide, 5.0 g of ethyl3-bromo-2-oxo-pentanoate, and 10 mL of toluene. Solids were collectedand washed with cold water after cooling of the NaOH solution. Heatingthese solids with citric acid as described followed by cooling andisolation of the resulting solids gave 410 mg (9% yield) of the titlecompound; ¹H NMR (CDCl₃, 300 MHz) δ8.06-8.03 (m, 2H), 7.49-7.43 (m, 3H),3.14 (q, 2H, J=8.0), 1.34 (t, 3H, J=8.0); low resolution MS (ES⁺)m/e217.8 (MH⁺).

Intermediate 2: 2-[5-methyl-2-phenyl-1,3-thiazol-4-yl]acetic acid methylester

A solution of 13.13 g (95.7 mmol) of thiobenzamide and 5.0 g (23.9 mmol)of methyl 4-bromo-3-oxo-pentanoate in 25 mL of dry toluene was heated at90° C. for 5 h. The solution was poured into EtOAc/water and the aqueousphase extracted with EtOAc. The organics were washed with brine, dried(MgSO₄), filtered, and concentrated. The crude oil was purified bysilica gel chromatography eluting with hexanes/EtOAc (3/1 to 2/1) toafford 4.14 g (70%) yield) of the title compound as a paleorange-colored oil: ¹H NMR (CDCl₃, 400 MHz) δ7.97 (m, 2H), 7.11 (m, 2H),3.73 (s, 3H), 3.56 (s, 2H), 2.36 (s, 3H).

Intermediate 2B: 2-[5-ethyl-2-phenyl-1,3-thiazol-4-yl]acetic acid

A suspension of 8.7 g (63.3 mmol) of thiobenzamide and 10 g (42.2 mmol)of ethyl 4-bromo-3-oxo-hexanoate in 45 mL of toluene was refluxed for 6hrs with Dean-Stark trap removal of water. Cooled, added methanol, andcontinued reflux for 1 h. Cooled, partially concentrated (˜½ volume),then 30 mL of 2.0 M NaOH solution was added. Stirred the mixture at 80°C. for 2 hrs before cooling and extraction of the aqueous with EtOAc.The aqueous phase was treated with 70 mL of 1.0 M citric acid withheating (70° C.) for 45 min. The mixture was extracted with EtOAc, andthe extracts were dried. over MgSO₄, filtered and concentrated to yielda yellow colored solid upon standing at ambient temperature (8.4 g, ˜80%yield); ¹H NMR (CDCl₃, 300 MHz) δ7.95-7.87 (m, 2H), 7.48-7.45 (m, 3H),3.86 (s, 2H), 2.85 (q, 2H, J=7.5), 1.36 (t, 3H, J=7.5).

Intermediate 2C: 5-ethyl-2-phenyl-1,3-thiazole4carboxylic acid

Intermediate 2C was prepared as described above for the preparation ofintermediate 2B from 4.61 g of thiobenzamide, 5.0 g of ethyl3-bromo-2-oxo-pentanoate, and 14 mL of toluene. Solids were collectedand washed with cold water after cooling of the NaOH solution. Heatingthese solids with citric acid as described followed by cooling andisolation of the resulting solids gave 3.74 g (72% yield) ofintermediate 2C; ¹H NMR (CDCl₃, 300 MHz) δ7913-7.91 (m, 2H), 7.51-7.50(m, 3H), 3.39 (q, 2H, J=7.8), 1.42 (t, 3H, J=7.8); low resolution MS(ES⁺)m/e 233.81 (MH⁺).

Intermediate 3: 2-[2-(4-fluorophenyl)-5-methyl-1,3-oxazol-4-yl]aceticacid methyl ester

A solution of 667 mg (4.80 mmol) of 4-fluorobenzamide and 1.0 g (4.80mmol) of methyl 4-bromo-3-oxo-pentanoate in 6 mL of dry toluene washeated at 120° C. for 16 h. The resulting dark slurry was cooled to rt,diluted with 10 mL of EtOAc, and washed with NaHCO₃ (1×10 mL). Theorganic layer was separated, dried (MgSO₄), and the solvents removedunder reduced pressure. Purification of the material by silica gel flashcolumn chromatography using hexane/EtOAc 4/1 as eluent to afford 308 mgof the title compound as a clear oil: ¹H NMR (CDCl₃, 400 MHz) δ7.97 (m,2H), 7.11 (m, 2H), 3.73 (s, 3H), 3.56 (s, 2H), 2.36(s, 3H).

Intermediate 3B: 2-[5-ethyl-2-(4-fluorophenyl)-1,3-oxazol-4-yl]aceticacid

The title compound was prepared from 5 g of 4-fluorobenzamide and 5.67 gof ethyl 4-bromo-3-oxo-hexanoate as described in example 2B to give 1.8grams of intermediate 3B as a solid: ¹H NMR (CDCl₃, 300 MHz) δ7.96 (dd,2H, J=8.8, 5.3), 7.11 (t, 2H, J=8.6), 3.61 (s, 2H), 2.69 (q, 2H, J=7.5),1.27 (t, 3H, J=7.5).

Intermediate 3C: 5-ethyl-2-(4-fluorophenyl)-1,3-oxazole-4-carboxylicacid

The title compound was prepared from 6.5 9 of 4-fluorobenzamide and 6.08g of ethyl 3-bromo-2-oxo-pentanoate (as described in example 2B) to give1.55 g (22%) of intermediate 3C as a solid: ¹H NMR (CDCl₃, 300 MHz)δ8.12-8.08 (m, 2H), 7.23-7.17 (m, 2H), 3.19 (q, 2H, J=7.5), 1.40 (t, 3H,J=7.5).

Intermediate 4: 2-[2-(4-fluorophenyl)-5-methyl-1,3-thiazol-4-yl]aceticacid ethyl ester

A mixture of 8.75 g (56.4 mmol) of 4-fluorobenzamide and 11.79 g (56.4mmol) of methyl 4-bromo-3-oxo-pentanoate in 45 mL of EtOH was refluxedfor 14 h. The solids formed upon cooling were removed via filtration andthe solvent removed under reduced pressure. The residue was taken intoEtOAc and washed with water, brine, and dried over MgSO₄. ¹H NMR of thecrude Intermediate 4 indicated purity sufficient to proceed into thenext stage of synthesis. ¹H NMR (CDCl₃, 400 MHz) δ7.97 (m, 2H) 7.11 (m,2H), 3.73 (s, 3H), 3.56 (s, 2H), 2.36 (s, 3H).

Intermediate 4B: 2-[5-ethyl-2-(4-fluorophenyl)-1,3-thiazol-4-yl]aceticacid

The title compound was prepared from 6.8 g of 4-fluorothiobenzamide and7.42 g of ethyl 4-bromo-3-oxo-hexanoate as described in example 2B togive 2.9 grams of intermediate 4B as a solid: ¹H NMR (CDCl₃, 300 MHz)δ7.96 (dd, 2H, J=8.8, 5.3), 7.11 (t, 2H, J=8.6), 3.61 (s, 2H), 2.69 (q,2H, J=7.5), 1.27 (t, 3H, J=7.5).

Intermediate 5: 2-[2-(4-methoxyphenyl)-5-methyl-1,3-oxazol-4-yl]aceticacid methyl ester

A mixture of 725 mg (4.80 mmol) of 4-methoxybenzamide and 1.0 g (4.80mmol) of methyl 4-bromo-3-oxo-pentanoate was heated neat at 120° C. for2 h. The resulting dark slurry was cooled to RT, diluted with 2 mL ofDCM and purified by silica gel flash column chromatography usinghexane/EtOAc (3/1) as eluent to afford 189 mg of the title compound as ayellow solid: ¹H NMR (CDCl₃, 400 MHz) δ7.92 (d, 2H, J=8.9), 6.93 (d, 2H,J=8.9), 3.85 (s, 3H), 3.73 (s, 3H), 3.56 (s, 2H), 2.34 (s, 3H); lowresolution MS (FAB)m/e 285 (MH⁺), 284 (M⁺).

Intermediate 6:2-[2-[4-trifluoromethylphenyl)-5-methyl-1,3-oxazol-4-yl]acetic acidmethyl ester

A mixture of 3.62 g (19.1 mmol) of 4-trifluoromethylbenzamide and 4.0 g(19 mmol) of methyl 4-bromo-3-oxo-pentanoate in 15 mL of toluene and 10mL of dioxane (with 2 mL of EtOH) was refluxed for 22 h. The solutionwas concentrated under reduced pressure. The residue was taken intoEtOAc and washed with water, brine, and dried over MgSO₄. The crudematerial was purified by silica gel chromatography (10%-40% EtOAc inhexanes) to yield 130 mg of a yellow solid: ¹H NMR (CDCl₃, 400 MHz) δ8.1(d, 2H, J=8.3), 7.65 (d, 2H, J=8.4), 3.75 (s, 3H), 3.58 (s, 2H), 2.39(s, 3H); low resolution MS (ES⁺) m/e 300.0 (MH⁺).

Intermediate 7:2-[2-(4-isopropoxyphenyl)-5-methyl-1,3-oxazol-4-yl]acetic acid ethylester

A mixture of 2.8 g (15.6 mmol) of 4-isopropoxybenzamide and 3.26 g (15.6mmol) of methyl 4-bromo-3-oxo-pentanoate in 10 mL of toluene and 1 mL ofEtOH was refluxed for 24 h. The solvents were removed and the cruderesidue purified directly via silica gel chromatography (4/1hexanes/EtOAc) to yield 1.31 g (28%) of Intermediate 6: ¹H NMR (CDCl₃,400 MHz) δ7.92 (d, 2H, J=8.9), 6.93 (d, 2H, J=8.9), 3.85 (s, 3H), 3.73(s, 3H), 3.56 (s, 2H), 2.34(s, 3H); low resolution MS (FAB)m/e 285(MH⁺).

Intermediate 8: 2-[5-methyl-phenyl-1,3-oxazol-4-yl]ethanol

To a solution of 330 mg (1.43 mmol) of intermediate 1 in 5 mL of THF at0° C. was added dropwise 1.43 mL (1.43 mmol) of 1.0 M LAH in Et₂Osolution. The solution as stirred at 0° C. for 1 hr, quenched by theaddition of 0.054 mL H₂O, 0.054 mL of 1.0 N NaOH solution, and 0.162 mLof H₂O, and MgSO₄ was added. The mixture was filtered, the filtrate wasconcentrated, and the crude oil dried under vacuum for several hours togive 280 mg of Intermediate 8 as a pale yellow-colored solid: ¹H NMR(CDCl₃, 400 MHz) d 7.97 (m, 2H), 7.42 (m, 3H), 3.92 (t, 2H, J=5.6), 2.72(t, 2H, J=5.6), 2.33 (s, 3H); low resolution MS (ES+)m/e 204 (MH⁺); TLCR_(f)=0.21 (1/1 hexanes/EtOAc)

Intermediate 8B: 2-[5-ethyl-2-phenyl-1,3-oxazol-4-yl]ethanol

The title compound was prepared (as described above for the preparationof

Intermediate 8 from intermediate 1B (710 mg, 2.74 mmol) and 125 mg LAHto give 480 mg (81% yield) of intermediate 8B: TLC R_(f)=0.21 (2/1hexanes/EtOAc); ¹H NMR (CDCl₃, 400 MHz) δ8.0-7.97 (m, 2H), 7.46-7.41 (m,3H), 3.92 (t, 2H, J=5.6), 3.33 (broad s, 1H), 2.75-2.66 (m, 4H), 1.27(t, 3H), J=7.6); low resolution MS (ES⁺)m/e 218.15 (MH⁺).

Intermediate 8C: 2-[2-phenyl-5-propyl-1,3-oxazol-4-yl]ethanol

The title compound was prepared (as described above for the preparationof Intermediate 8) from intermediate 1C (820 mg, 3.0 mmol) and 137 mgLAH to give 360 mg (52% yield) of intermediate 8C: TLC R_(f)=0.29 (2/1hexanes/EtOAc); ¹H NMR (CDCl₃, 400 MHz) δ7.91 (m, 2H), 7.39-7.32 (m,3H), 3.86 (t, 2H, J=5.6), 2.68-2.55 (m, 2H), 4.48-2.41 (m, 2H),1.68-1.53 (m, 2H), 0.91 (t, 3H, J=7.6); low resolution MS (ES⁺)m/e232.14 (MH⁺).

Intermediate 8D: [5-methyl-2-phenyl-1,3-oxazol-4-yl]methanol

The title compound was prepared via LAH reduction of intermediate 1D.Thus, 670 mg of Intermediate 1D (3.30 mmol) was stirred with 165 mg ofLAH at 23° C. for two hours. Silica gel chromatography gave 120 mg (19%yield) of Intermediate 8D: TLC R_(f)=0.28 (2/1 hexanes/EtOAc); ¹H NMR(CDCl₃, 300 MHz) δ8.0-7.97 (m, 2H), 7.49-7.41 (m, 3H), 4.59 (s, 2H),4.18-4.05 (broad s, 1H), 2.38 (s, 3H); low resolution MS (ES⁺)m/e 190.1(MH⁺).

Intermediate 8E: 3-[5methyl-2-phenyl-1,3-oxazol-4-yl]propanol

The title compound was prepared from intermediate 8 via a 1-carbonhomologation sequence as follows: The mesylate (3.88 g, 1.38 mmol) ofalcohol Intermediate 8 (from Et₃N, methanesulfonyl chloride, THF, 0° C.)was heated to 120° C. with 1.08 g (16.6 mmol) of KCN for 14 hr. Aqueouswork-up and silica gel chromatography (EtOAc/hexanes) gave 860 mg (30%)of cyanide intermediate. Hydrolysis to the acid intermediate wasaccomplished in refluxing EtOH/water for 2.5 hrs with NaOH (650 mg).Acidification of the aqueous phase gave 580 mg (62% yield) of the acid.Reduction with LAH (95 mg, 3.0 mmol) in Et₂O for 3 hrs followed bysilica gel chromatography provided 370 mg (68% yield) of Intermediate8E: TLC R_(f)=0.14 (2/1 hexanes/EtOAc);¹H NMR (CDCl₃, 400 MHz)δ7.98-7.93 (m, 2H), 7.45-7.37 (m, 3H), 3.75 (t, 2H, J=8.7), 3.36 (br s,1H), 2.64 (t, 2H, J=6.9), 2.33 (s, 3H), 1.94-1.85 (m, 2H); lowresolution MS (ES⁺)m/e 218.17 (MH⁺).

Intermediate 8F: 3-[5-ethyl-2-phenyl-1,3-oxazol-4-yl]propanol

Intermediate 8F was prepared from intermediate 8B via a one carbonhomologation procedure as described for the preparation of intermediate8E. Thus, 495 mg of alcohol intermediate 8B was converted tointermediate 8F via mesylate (380 mg), cyanide (355 mg), and acid (280mg) intermediates. Borane reduction (THF, 0° C., 6.5 mL of 1.0 M BH₃/THFcomplex) on 273 mg of acid intermediate gave 215 mg of alcoholintermediate 8F; ¹H NMR (CDCl₃, 300 MHz) δ8.05-8.01 (m, 2H), 7.48-7.44(m, 3H), 3.79 (t, 2H, J=5.8 ), 2.78-2.67 (m, 4H), 1.97-1.91 (m, 2H),1.31 (t, 3H, J=7.5); low resolution MS (ES⁺)m/e 231.91 (M⁺); TLCR_(f)=0.49 (1/2 hexanes/EtOAc).

Intermediate 8G: [5-ethyl-2-phenyl-1,3oxazol-4-yl]methanol

Intermediate 8G was prepared (as described below for intermediate 9B)from 410 mg of intermediate 1E to give 335 mg (87%) of the titlecompound; ¹H NMR (CDCl₃, 300 MHz) δ7.96-7.940 (m, 2H), 7.39-7.37 (m,3H), 4.54 (s, 2H), 2.71 (q, 2H, J=7.5), 2.38 (br s, 1H), 1.25 (t, 3H,J=7.5); low resolution MS (ES⁺)m/e 203.94 (MH⁺).

Intermediate 9: 2-[5-methyl-2-phenyl-1,3-thiazol-4-yl]ethanol

To a 0° C. stirred solution of 6.11 g (24.7 mmol) of ester Intermediate2 in 100 mL of THF was added 935 mg (25 mmol) of LAH. The reaction wasstirred for 20 minutes at 20° C., cooled to 0° C., and quenched withwater. The solids were filtered, washed with Et₂O, and the filtrate wasdried (MgSO₄). Silica gel chromatography with EtOAc in hexanes (40% to50%) gave 2.33 g (38% yield) of Intermediate 9: ¹H NMR (CDCl₃, 400 MHz)δ7.85 (m, 2H), 7.42 (m, 3H), 3.99 (m, 3), 2.90 (m, 2H), 2.41 (s, 3H);low resolution MS (ES+)m/e 220.1 (MH⁺); TLC R_(f=)0.43 (1/1hexanes/EtOAc).

Intermediate 9B: 2-[5-ethyl-2-phenyl-1,3-thiazol-4-yl]ethanol

To a THF (15 mL) solution of 4.0 g (16.2 mmol) of intermediate 2B at 0°C. was added dropwise over 10 minutes 57 mL of 1.0 M BH₃-THF complex inTHF. Stirred at 35-40° C. for 3 h before cooling to 0° C. and quenchingwith 70 mL of MeOH. Concentrated, taken into 50 mL of n-butanol andrefluxed for 45 min. The solution was concentrated and the residuecollected was purified by silica gel chromatography. Elution with 20-50%EtOAc in hexanes gave 2.4 g (64% yield) of a yellow viscous oil afterconcentration of the pooled product fractions and drying under vacuum:¹H NMR (CDCl₃, 300 MHz) δ7.86-7.83 (m, 2H), 7.41-7.34 (m, 3H), 3.96 (t,2H, J=5.5), 2.89 (t, 2H, J=5.5), 2.77 (q, 2H, J=7.5), 1.27 (t, 3H,J=7.5).

Intermediate 9C: [5-ethyl-2-phenyl-1,3-thiazol-4-yl]methanol

Intermediate 9C was prepared (as described above for intermediate 9B)from 3.74 g of intermediate 2C to give 2.45 g (70%) of the titlecompound; ¹H NMR (CDCl₃, 300 MHz) δ793-7.90 (m, 2H), 7.47-7.43 (m, 3H),4.75 (s, 2H), 3.02 (br s, 1H), 2.89 (q, 2H, J=7.2), 1.35 (t, 3H, J=7.2);low resolution MS (ES⁺)m/e 219.88 (MH⁺).

Intermediate 10: 2-[2-(4-fluorophenyl)-5-methyl-1,3-oxazol-4-yl]ethanol

To a 0° C. stirred solution of 380 mg (1.44 mmol) of ester Intermediate3 in 10 mL of THF was added 55 mg (1.44 mmol) of LAH. The reaction wasstirred for 20 minutes at 20° C., cooled to 0° C., and quenched withsaturated aqueous NH₄Cl solution. The solids were filtered, washed withEt₂O, and the filtrate was dried (MgSO₄). Silica gel chromatography withEtOAc/hexanes (1/2 to 2/1) as eluent gave 175 mg (55% yield) ofintermediate 10: ¹H NMR (CDCl₃, 400 MHz) δ7.96 (m, 2H), 7.12 (m, 2H),3.92 (d, 2H, J=5.0), 3.21 (s, 1H), 2.71 (t, 2H, J=5.6), 2.32 (s, 3H);low resolution MS (FAB)m/e 221 (M⁺); TLC R_(f)=0.20 (1/1 hexanes/EtOAc).

Intermediate 10B: 2-[5-ethyl-2-(4-fluorophenyl)-1,3-oxazol-4-yl]ethanol

The title compound was prepared as described above for example 9B. From1.3 g of intermediate 3B was prepared 1.14 g (94%) of intermediate 10Bas a yellow-colored, viscous oil; ¹H NMR (CDCl₃, 400 MHz) δ7.98-7.94 (m,2H), 7.10 (t, 2H, J=8.7), 3.89 (t, 2H, J=5.6), 2.71 (t, 2H, J=5.7), 2.66(t, 2H, J=7.5), 1.25 (t, 3H, J=7.5); low resolution MS (ES+)m e 236.17(MH⁺); TLC R_(f)=0.37 (1/1 hexanes/EtOAc)

Intermediate 10C: 3-[5-ethyl-2-fluorophenyl)-1,3-oxazol-4-yl]propanol

Intermediate 10C was prepared from intermediate 10B via a one carbonhomologation procedure as described for the preparation of intermediate8E. Thus, 720 mg of alcohol intermediate 10B was converted tointermediate 10C via mesylate (828 mg), cyanide (495 mg), and acid (440mg) intermediates. Borane reduction (THF, 0° C. 6.5 mL of 1.0 M BH₃/THFcomplex) instead of LAH reduction on 430 mg of acid intermediate gave320 mg of alcohol intermediate 10C; ¹H NMR (CDCl₃, 400 MHz) δ7.98-7.93(m, 2H), 7.09 (t, 2H, J=8.6), 3.72 (t, 2H, J=5.8), 2.70-2.56 (m, 4H),1.91-2H), 1.24 (t, 3H, J=7.5); low resolution MS (ES+)m/e 250.15 (MH⁺);TLC R_(f)0.55 (1/2 hexanes/EtOAc).

Intermediate 10D: [5-ethyl-2-(4-fluorophenyl)-1,3-oxazol-4-yl]methanol

The title compound was prepared as described above for example 9B. From1.52 g of intermediate 3C was prepared 735 mg (51%) of intermediate 10D;¹H NMR (CDCl₃, 300 MHz) δ8.05-8.04 (m, 2H), 7.18-7.16 (m, 2H), 4.64 (s,2H), 2.82-2.78 (m, 2H), 2.30 (br s, 1H), 1.35-1.31 (m, 3H); lowresolution MS (ES+)m/e 221.94 (MH⁺); TLC R_(f)=0.60 (1/2 hexanes/EtOAc).

Intermediate 11: 2-[2-(4-fluorophenyl)-5-methyl-1,3-thiazol-4-yl]ethanol

The title compound was prepared from crude ester Intermediate 4 and 1.07g of LAH as described above for the preparation of Intermediate 10 toyield 2.8 g of Intermediate 11 (21% yield over two steps, preparation ofIntermediates 4 plus 11): ¹H NMR (CDCl₃, 400 MHz) δ7.96 (m, 2H), 7.12(m, 2H), 3.92 (d, 2H, J=5.0), 3.21 (s, I H), 2.71 (t, 2H, J=5.6), 2.32(s, 3H); resolution MS (FAB)m/e 221 (M⁺).

Intermediate 11B: 2-[5-ethyl-2-(4-fluorophenyl)-1,3-thiazol-4-yl]ethanol

The title compound was prepared as described above for example 9B. From2.7 g of intermediate 4B was prepared 1.75 g (68%) of intermediate 11Bas a colorless, viscous oil; ¹H NMR (CDCl₃, 400 MHz) δ7.85-7.80 (m, 2H),7.07 (t, 2H, J=8.7), 3.95 (t, 2H, J=5.6), 2.88 (t, 2H, J=5.5), 2.77 (q,2H, J=7.5), 1.27 (t, 3H, J=7.5); low resolution MS (ES+)m/e 252.17(MH⁺); TLC R_(f)=0.47 (1/1 hexanes/EtOAc)

Intermediate 12: 2-[24(4-methoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethanol

To a stirring solution of 185 mg (0.71 mmol) of Intermediate 42 in 5 mLof THF at 0° C. was added 0.71 mL (0.71 mmol, 1.0 equiv) of a 1.0 Msolution of LiAlH₄ in THF. The resulting solution was stirred at RT for45 min then cooled to 0° C. and quenched by careful addition of 0.027 mLof H₂O, followed by addition of 0.027 mL of 15% NaOH and 0.080 mL ofH₂0. The resulting slurry was filtered to remove the solids and thefiltrate was concentrated under reduced pressure to afford 164 mg of thetitle compound as a light yellow oil: ¹H NMR (CDCl₃, 400 MHz) δ7.92 (d,2H, J=8.8), 6.94 (d, 2H, J=8.8), 3.92 (dt, 2H, J=5.7, 11.5), 3.86 (s,3H), 3.35 (t, 1H, J=6.2), 2.71 (t, 2H, J=5.7) 2.32 (s, 3H).

Intermediate 13:2-[2-(4-trifluoromethylphenyl)-5-methyl-1,3-oxazol-4-yl]ethanol

The title compound was prepared from 390 mg of ester Intermediate 6 (asdescribed above for the preparation of Intermediate 10) to yield 170 mgof Intermediate 13: TLC R_(f)=0.24 (1/1 hexanes/EtOAc), ¹H NMR (400 MHz,CDCl₃) δ8.08 (d, 2H, J=8.2), 7.68 (d, 2H, J=8.4), 3.93 (q, 2H, J=11.4,5.8), 2.99 (t, 1H, J=6.0), 2.74 (t, 2H, J=5.8), 1.56 (s, 3H).

Intermediate 14:2-[2-(4-isopropoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethanol

The title compound was prepared from 1.3 g of ester Intermediate 7 (asdescribed above for the preparation of Intermediate 10) to yield 540 mgof Intermediate 14: TLC R_(f)=0.21 (1/1 hexanes/EtOAc), ¹H NMR (400 MHz,CDCl₃) δ7.87 (d, 2H, J=8.8), 6.9 (d, 2H, J=9.0), 4.6 (hept, 1H, J=6.0),3.9 (q, 2H, J=11.4, 5.7), 3.35 (t, 1H, J=6.0), 2.69 (t, 2H, J=5.6), 2.3(s, 3H), 1.35 (d, 6H, J=6.0).

Intermediate 15:5-[24(methanesulfonyloxy)ethyl]-4-methyl-2-phenyl-1,3-oxazole

To a solution of 9.41 g (46.3 mmol) of alcohol Intermediate 8 in CH₂Cl₂(300 mL) at 0° C. was added 3.94 mL (50.9 mmol) of methanesulfonylchloride followed by 7.75 mL (55.6 mmol) of triethylamine. After 1 hrwith gradual warming to 20° C., the solution was washed with water (3×),brine (1×), and dried over MgSO₄. Concentration gave 12.92 g (99%) ofIntermediate 15 homogeneous by TLC analysis: (R_(f)=0.24, 1/1hexanes/EtOAc); ¹H NMR (CDCl₃, 400 MHz) d 7.97 (m, 2H), 7.43 (m, 3H),4.53 (t, 2H, J=6.5), 2.95 (s 3H), 2.95 (t, 2H, J=6.5), 2.36(s, 3H); lowresolution MS (ES+)m/e 281.9 (MH⁺); TLC R_(f)=0.35 (1/1 hexanes/EtOAc)

Intermediate 16: 1 (phenyl)-1,3-pentanedione

The title compound was prepared according to Popio, V. V. et al.Synthesis (March 1991), pp 195-197. To a stirred suspension of NaH (1.2g, 50 mmol) and ethyl propionate (5.73 mL. 50 mmol) in 20 mL THF at 20°C. was added EtOH (2 drops), acetophenone (3.0 g, 25 mmol) in 20 mL ofTHF, and dibenzo-18-crown-6 (150 mg, 0.4 mmol) in 20 mL of THF. Stirredfor 30 min, then at reflux for 1 hr. Cooled (0° C.), then added 25 mL of10% H₂SO₄ solution and the aqueous was extracted with Et₂O. The organicswere washed with H₂O, aqueous Na₂CO₃, and brine. The solution was driedover Na₂SO₄ and concentrated. Purification by silica gel chromatography(1% to 10% EtOAc in hexanes) gave 4.0 g of Intermediate 16 as a thinoil. ¹H NMR indicated an ˜10:1 mixture of tautomers favoring the enolform: ¹H NMR (400 MHz, CDCl₃, enol form) δ7.87 (m, 2H), 7.52-7.4 (m,3H), 6.17 (s, 1H), 2.47 (q, 2H, J=7.5), 1.21 (t, 3H, J=7.5)

Intermediates 17,18, and 20-33 were prepared analogous to the methoddescribed above for the preparation of Intermediate 16. Intermediate 17:1-phenyl)-1,3-hexanedione

The title compound was prepared (as described above for Intermediate 16)from 3.0 g of acetophenone and 5.8 g of ethyl butyrate to yield 4.0grams of Intermediate 17 as an oil: TLC R_(f)=0.51 (1/9 EtOAc/Hexanes);¹H NMR (400 MHz, CDCl₃) δ7.88 (m, 2H), 7.48 (m, 3H), 6.17 (s, 1H), 2.4(t, 2H, J=7.6), 1.72 (q, 2H, J=7.6), 1.0 (t, 3H, J=7.2); low resolutionMS (ES+)m/e 213.0 (M+Na⁺).

Intermediate 18: 1-(phenyl)-1,3-heptanedione

The title compound was prepared (as described above for Intermediate 16)from 2.2 g (18.3 mmol) of acetophenone and 4.51 g (35 mmol) of ethylvalerate to yield 2.6 grams of Intermediate 18:: TLC R_(f)=0.52 (1/9EtOAc/Hexanes); ¹H NMR (400 MHz, CDCl₃) δ7.87 (m, 2H), 7.48 (m, 3H),6.17 (s,1H), 2.42 (t, 2H, J=7.6), 1.67 (m, 2H), 1.4 (m, 2H), 0.95 (t,3H, J=7.2); low resolution MS (ES+)m/e 205.1 (MH+), 227.1 (M+Na⁺).

Intermediate 19: 1(phenyl)-1,3decanedione

To a solution of 1 g (6.1 mmol) of benzoylacetone in 6 mL of THF at −78°C. was added 8.2 mL (12.3 mmol) of a 1.5 M LDA solution in THF. Warmedto 0° C. over 2 h, then 2.6 mL (12.3 mmol) of 1-iodohexane was added.The mixture was stirred at rt for 3 h before quenching with saturatedaqueous NH₄Cl solution and dilution with Et₂O. The organics were dried(Na₂SO₄), filtered, concentrated, and purified by silica gelchromatography (15/1 hexanes/Et₂O) to yield Intermediate 19: TLCR_(f)=0.52 (1/10 Et₂O/Hexanes); ¹H NMR (400 MHz, CDCl₃, enol form) δ7.88(m, 2H), 7.54-7.43 (m, 3H), 6.17 (s, 1H), 2.42 (t, 2H, J=7.6), 1.66 (m,2H), 1.4-1.25 (m, 8H), 0.85 (m, 3H); low resolution MS(ES+) m/e 269.0(M+Na⁺).

Intermediate 20: 1 (2-Fluorophenyl)-1,3-butanedione

The title compound was prepared (as described above for Intermediate 16)from 2.0 g of 2′-fluoroacetophenone and 2.86 mL of EtOAc to yieldIntermediate 20: ¹H NMR (400 MHz, CDCl₃, enol form) δ7.70 (dt, 1H.J=1.79, 7.69), 7.45 (m, 1H), 7.24 (m, 1H), 7.10 (m, 1H), 6.28 (s, 1H),2.20 (s, 3H).

Intermediate 21: 1(3methylphenyl)-1,3-butanedione

The title compound was prepared (as described above for Intermediate 16)from 2.72 mL of 3′-methylacetophenone and 3.95 mL of EtOAc to yield 2.94grams of Intermediate 21 as an oil: ¹H NMR (400 MHz, CDCl₃enol form)δ7.70 (m, 2H), 7.34 (m, 2H), 6.17 (s, 1H), 2.41 (s, 3H), 2.20 (s, 3H);low resolution MS (ES)m/e 177.1 (MH⁺).

Intermediate 22:1-(4-methoxyphenyl)-1,3-butanedione

The title compound was prepared (as described above for Intermediate 16)from 3.0 g of 4′-methoxyacetophenone and 3.95 mL of EtOAc. Purificationby recrystallization from toluene/hexane afforded the title compound: ¹HNMR (400 MHz, CDCl₃, enol form) δ7.70 (d, 2H, J=8.20), 7.34 (d, 2H,J=8.20), 6.17 (s, 1H), 3.87 (s, 3H), 2.17 (s, 3H); low resolution MS(ES)m/e 193.1 (MH⁺)

Intermediate 23: 142-hydroxyphenyl)-1,3-butanedione

The title compound was purchased from Aldrich Chemical Co.

Intermediate 24: 1-(4-trifluoromethylphenyl)-1,3-butanedione

The title compound was prepared (as described above for Intermediate 16)from 51.43 g of 4′-trifluoroacetophenone and 53.4 mL of EtOAc to yield35.78 g of Intermediate 24: TLC analysis: R_(f)=0.70 (2/1,hexanes/EtOAc), ¹H NMR (400 MHz, CDCl₃, enol form) δ7.96 (d, 2H, J=7.0),7.7 (d, 2H, J=7.0), 6.2 (s, 1H), 2.23 (s, 3H).

Intermediate 25: 144-trifluoromethylphenyl)-1,3-pentanedione

The title compound was prepared (as described above for Intermediate 16)from 1.5 g of 4′-trifluoromethylacetophenone and 1.54 mL of methylpropionate to yield 0.69 g of intermediate 25: TLC analysis: R_(f)=0.75(2/1, hexanes/EtOAc), ¹H NMR (400 MHz, CDCl₃, enol form) δ7.92-7.86 (m,2H), 7.12 (t, 2H, J=8.6), 6.1 (s, 1H), 2.45 (q, 2H, J=7.5), 1.21 (t, 3H,J=7.5).

Intermediate 26: 1-4(4-Fluorophenyl)-1,3-butanedione

The title compound was prepared (as described above for Intermediate 16)from 2.42 mL of 4′-fluoroacetophenone and 3.95 mL of EtOAc to yieldIntermediate 26 as an oil: ¹H NMR (400 MHz, CDCl₃, enol form) δ7.89 (dd,2H, J=8.90, 5.40), 7.13 (dd, 2H, J=17.2, 8.60), 6.13 (s, 1H), 2.19 (s,3H).

Intermediate 27: 1-(4-methylphenyl)-1,3-butanedione

The title compound was prepared (as described above for Intermediate 16)from 2.0 g of 4′-methylacetophenone and 2.9 mL of EtOAc to yield 1.68grams of Intermediate 27: TLC analysis: R_(f)=0.61 (5/1, hexanes/EtOAc),¹H NMR (400 MHz, CDCl₃, enol form) δ7.72 (d, 2H, J=8.2), 7.24 (d, 2H,J=7.4), 6.15 (s, 1H), 2.4 (s, 3H), 2.2 (s, 3H).

Intermediate 28: 1-(4-chlorophenyl)-1,3-butanedione

The title compound was prepared (as described above for Intermediate 16)from 2.0 g of 4′-chloroacetophenone and 2.53 mL of EtOAc to yield 1.7grams of Intermediate 28: TLC analysis: R_(f)=0.73 (2/1, hexanes/EtOAc);¹H NMR (400 MHz, CDCl₃, enol form) δ7.82 (d, 2H, J=8.0), 7.42 (d, 2H,J=8.0), 6.13 (s, 1H), 2.2 (s, 3H).

Intermediate 29: 1(4-isopropoxyphenyl)-1,3-butanedione

The title compound was prepared (as described above for Intermediate 16)from 2.42 g of 4′-isopropoxyacetophenone and 2.65 mL of EtOAc to yield2.25 grams of Intermediate 29: TLC analysis: R_(f)=0.73 (2/1,hexanes/EtOAc); ¹H NMR (400 MHz, CDCl₃, enol form) δ7.84 (d, 2H, J=8.9),6.9 (d, 2H, J=9.0), 6.1 (s, 1H), 4.62 (hept, 1H, J=6.0), 2.16 (s, 3H),1.36 (d, 6H, J=6.0).

Intermediate 30:1-(2-chlorophenyl)-1,3-butanedione

The title compound was prepared (as described above for Intermediate 16)from 2.0 g of 2′-chloroacetophenone and 2.53 mL of EtOAc to yield 0.5 gof Intermediate 30: TLC analysis: R_(f)=0.76 (2/1, hexanes/EtOAc); ¹HNMR (400 MHz, CDCl₃, enol form) δ7.6-7.55 (m, 1H), 7.45-7.43 (m, 1H),7.4-7.32 (m, 1H), 6.05 (s, 1H), 2.18 (s, 3H).

Intermediate 31: -(1,3-thienyl)-1,3-butanedione

The title compound was prepared (as described above for Intermediate 16)from 1.5 g of 3-acetylthiophene and 2.32 mL of EtOAc to yield 1.28 gramsof Intermediate 31 as a yellow oil: TLC R_(f)=0.65 (2/1, hexanes/EtOAc);¹H NMR (400 MHz, CDCl₃, enol form major, ˜85:15) δ8.0 (m, 1H), 7.45 (m,1H), 7.35 (m, 1H), 6.0 (s, 1H), 2.18 (s, 3H).

Intermediate 32: -(4-Fluorophenyl)-1,3-pentanedione

The title compound was prepared (as described above for Intermediate 16)from 0.525 g of 4′-fluoroacetophenone and 0.73 mL of methyl propionateto yield 120 mg of Intermediate 32: TLC analysis: R_(f)=0.77 (2/1,hexanes/EtOAc); ¹H NMR (400 MHz, CDCl₃, enol form) δ7.98 (d, 2H, J=8.3),7.7 (d, 2H, J=8.3), 6.12 (s, 1H), 1.55 (s, 3H); low resolution massspectrum (ES+) 195 (MH+)

Intermediate 33: -(4cyclohexyl)-1,3-butanedione

The title compound was prepared as described above from 1.5 g ofcyclohexyl methyl ketone and 2.32 mL of EtOAc to yield 1.06 grams ofIntermediate 33 as a yellow oil: TLC R_(f)=0.65 (3/1, hexanes/EtOAc); ¹HNMR (400 MHz, CDCl₃, enol form) δ5.5 (s, 1H), 2.19-2.12 (m, 1H), 2.08(s, 3H), 1.85-1.55 (m, 5H), 1.41-1.15 (m, 5H).

Intermediate 34: 1-(2-pyrazinyl)-1,3-butanedione

To a solution of methyl 2-pyridazinecarboxylate (1.5 g, 10.86 mmol) in 3mL of acetone and 10 mL of THF was slowly added 590 mg (10.86 mmol) ofNaOMe and the resulting mixture was refluxed for 4 hr. The mixture wasfiltered, the filtrate was acidified and extracted with CH₂Cl₂, and theorganics 10 were dried over MgSO₄ to yield 940 mg (53%) homogeneous byTLC: R_(f)=0.5 (2/1, EtOAc/hexanes); ¹H NMR (400 MHz, CDCl₃, enol form)δ9.27 (d, 1H, J=1.4), 8.7 (d, 1H, J=2.4), 8.6 (t, 1H, J=1.8), 2.26 (s,3H).

Intermediate 35: 1-(2-pyridinyl)-1,3-butanedione

Intermediate 36 was prepared as described above for Intermediate 35 from2.0 g of methyl 2-pyridylcarboxylate and 4.0 mL of acetone to yield 1.08g of the title compound (45% yield) as a light brown oil: TLC analysis:R_(f)=0.73 (2/1, hexanes/EtOAc); ¹H NMR (400 MHz, CDCl₃, mixture ofenol/non-enol forms ˜80/20) δ8.66 (m, 1H), 8.05 (m, 1H), 7.85 (m, 1H),7.46 (m, 1H), 6.8 (s, 1H), 2.24 (s, 3H), (non-enol form singletsobserved at 4.28 and 2.35).; low resolution mass spectrum (ES+) 164.1(MH+).

Intermediate 36: 1-(2,3,4-trifluorophenyl)-2-butyn-1-one

Propynyllithium (720 mg, 14.05 mmol) was added to a 0° C. stirredsolution of 1.5 g (9.37 mmol) of 2,3,4-trifluorobenzaldehyde and thesolution was allowed to stir for 1 h with warming to ambienttemperature. The solution was diluted with EtOAc and washed with H₂O andbrine. The organics were dried over MgSO₄ and concentrated (yield ofintermediate alcohol, 1.88 g). The crude product was stirred in 30 mL ofCH₂Cl₂ with 4 g of activated MnO₂ at 20° C. for 2.5 h. The mixture wasfiltered through a pad of celite/silica gel and concentrated to yield1.31 g (47% overall yield) of crude product homogeneous by TLC analysis:R_(f)=0.6 (2/1, hexanes/EtOAc); ¹H NMR (300 MHz, CDCl₃) δ7.9-7.8 (m,1H), 7.1-6.95 (m, 1H), 2.13 (s, 3H).

Intermediates 37-43 were prepared analogous to the method describedabove for the preparation of Intermediate 36.

Intermediate 37:1-(2-fluoro-3-trifluoromethylphenyl)-1,3-pentanedione

The title compound was prepared (as described above for intermediate 36)from 0.5 g of 2′-fluoro-3′-trifluoromethylbenzaldehyde and 1.03 g ofMnO₂ to yield 0.46 g (75% overall yield) of Intermediate 37: ¹H NMR (400MHz, CDCl₃) δ8.19 (m, 1H), 7.84 (m, 1H), 7.32 (m,₁H), 2.1 (s, 3H).

Intermediate 38: 1-(2,4,5-trifluorophenyl)-2-butyn-1-one

Intermediate 38 was prepared (as described above for intermediate 36)from 1-propynyllithium, 0.5 g of 2′,4′,5′-trifluorobenzaldehyde, and0.87 g of MnO₂ to yield 0.39 g (63% overall yield) of the titlecompound: ¹H NMR (400 MHz, CDCl₃) δ7.91-7.82 (m, 1H), 7.05-6.96 (m, 1H),2.14 (s, 3H). For the alcohol intermediate; ¹H NMR (400 MHz, CDCl₃)δ7.54-7.48 (m, 1H), 6.97-6.88 (m, 1H), 5.64 (s, 1H), 1.91 (s, 3H).

Intermediate 39: 1-(2,4-difluorophenyl)-2-butyn-1-one

Intermediate 39 was prepared (as described above for intermediate 36)from 1-propynyllithium, 500 mg of 2′,4′-difluorobenzaldehyde, and 1.5 gof MnO₂ to yield 400 mg of the title compound homogeneous by TLC(R_(f)=0.63, 2/1 hexanes/EtOAc); ¹H NMR (400 MHz, CDCl₃) δ8.13-8.06 (m,1H), 6.99-6.94 (m, 1H), 6.91.6.85 (m, 1H), 2.14 (s, 3H).

Intermediate 40: 1-(2,3-difluorophenyl)-2-butyn-1-one

Intermediate 40 was prepared (as described above for intermediate 36)from 1-propynyllithium, 500 mg of 2,3-difluorobenzaldehyde, and 1.5 g ofMnO₂ to yield 440 mg of the title compound homogeneous by TLC(R_(f)=0.5, 2/1 hexanes/EtOAc); ¹H NMR (400 MHz, CDCl₃) δ7.82-7.86 (m,1H), 7.43-7.35 (m 1H), 7.22-7.15 (m, 1H), 2.15 (s, 3H).

Intermediate 41: 1-(4-nitrophenyl)-2-butyn-1-one

Intermediate 41 was prepared (as described above for intermediate 36)from 1-propynyllithium, 1.0 gram of 4′-nitrobenzaldehyde, and 1.0 g ofMnO₂ to yield 430 mg of the title compound homogeneous by TLC analysis:R_(f)=0.55 (2/1, hexanes/EtOAc), ¹H NMR (400 MHz, CDCl₃) δ8.32-8.28 (m,4H), 2.12 (s, 3H).

Intermediate 42: 1-(3-nitrophenyl)-2-butyn-1-one

Intermediate 42 was prepared (as described above for Intermediate 36)from 1-propynyllithium and 0.5 g of 3′-nitrobenzaldehyde and 1.5 g MnO₂to yield 280 mg of the title compound: TLC analysis: R_(f)=0.50 (2/1,hexanes/EtOAc), ¹H NMR (400 MHz, CDCl₃) δ8.95 (t, 1H, J=1.8), 8.47 (t,1H, J=1.7), 8.44 (t, 1H, J=1.7), 7.7 (t, 1H, J=8.0), 2.23 (s, 3H).

Intermediate 43: 1-(2-thiazolyl)-2-butyn-1-one

Intermediate 43 was prepared (as described above for Intermediate 36)from 1-propynyllithium, 2-thiophene carboxaldehyde (108 mg) and 300 mgof MnO₂to yield 65 mg of the title compound : TLC analysis: R_(f)=0.50(1/1, hexanes/EtOAc); ¹H NMR (400 MHz, CDCl₃) δ8.1 (d, 1H, J=2.8), 7.71(d, 1H, J=2.9), 2.21 (s, 3H); low resolution mass spectrum (ES+) 152.1(MH+).

Intermediate 44: 3-Bromo-4,4,4-trifluoro-1-phenylbut-2-en-1-one (mixtureof E- and Z-isomers, ˜85:15)

To a solution of 7.58 g (28.9 mmol) of triphenylphosphine in 60 mL ofCH₂Cl₂ at 0° C. was added 1.49 mL (28.9 mmol) of bromine dropwise. Thesolution was warmed to ambient temperature and 5.0 g (23.1 mmol) oftrifluoroacetyl-acetophenone in 25 mL CH₂Cl₂ and 6.45 mL (46.3 mmol) oftriethylamine were added. The mixture was stirred for two hours until nofurther change was observed by TLC analysis (3/1 hexanes/EtOAc). Themixture was washed with 1.0 N HCl, H₂O, and brine. The organics weredried over MgSO₄, concentrated, and the residue purified by silica gelchromatography (20/1 hexanes/EtOAc) to give 1.6 g of impure material and1.15 g (25% yield) of Intermediate 44 as an oil: TLC R_(f)=0.74 (3/1,hexanes/EtOAc); ¹H NMR (400 MHz, CDCl₃) δ7.95-7.5 (series of multiplets,5H); ¹⁹F NMR (282 MHz, CDCl₃) singlet, δ−100.5 ppm)

Intermediate 45:(2S)-2-amino-3-{4-[2-(5-methyl-2-phenyl-1,3oxazol-4-yl)ethoxy]phenyl}propanoicacid

Dianion coupling method: To a solution of 5.4 g (19.3 mmol) ofN-(Boc)-L-Tyrosine in 5 mL of DMSO and 10 mL of H₂O was added 1.7 g(42.5 mmol) of freshly ground NaOH pellets. The mixture was heated to55-60° C. and a solution of 6.5 g (23.1 mmol) of mesylate intermediate15 in 10 mL of DMSO was added dropwise over ˜5 min. The resultingmixture was stirred vigorously for 8 hr at 55-60° C., cooled to 20° C.,and poured into 100 mL of H₂O and extracted with Et₂O (2×50 mL). Theaqueous phase was separated and acidified to pH˜2-3 with glacial aceticacid/HCl. The resulting slurry was extracted with EtOAc several times,dried (MgSO₄), and the organics were concentrated to a tan oil. The oilwas triturated with hexanes/EtOAc (3/1) to give a cream-colored solid.This solid was recrystallized from hot MeOH/H₂O (2.5/1) to yield 5.5 g(61% yield) of Boc-protected intermediate as a white solid after dryingin a vacuum oven at 60° C. for ˜14 hr. To a solution of 43.54 g (93.3mmol) of the above Boc-protected intermediate in 150 mL of dioxane wasadded 200 mL of 4.0 N HCl in dioxane solution and the mixture wasstirred over 7 hr with the gradual formation of a white solid. Thesolids were filtered (rinsing with Et₂O), suspended into 1 L of H₂O, andthe pH was adjusted to pH˜5 with 15% NaOH. The resulting white solidswere collected via filtration, washed with H₂O and CH₃CN, and driedovernight at 70° C. in a vacuum oven to give 32.9 g (96%) ofintermediate 45 as a white solid: ¹H NMR (DMSO-d₆, 300 MHz) δ7.95 (m,2H), 7.55 (m, 3H), 7.22 (d, 2H, J=8.5), 6.9 (d, 2H, J=8.5), 4.21 (t, 2H,J=6.4), 3.1 (dd, 1H, J=14.3, 4.1), 4.17 (m, 1H), 2.96 (t, 2H, J=6.6),2.83 (dd, 1H, J=14.3, 8.4), 2.53 (s, 3H), α-methine proton assumed underH₂O peak:; low resolution MS (ES+)m/e 367.4 (MH⁺);

Alternative Mitsunobu Coupling Method

To a solution of 4.46 g (21.9 mmol) of alcohol Intermediate 8, 5.88 g(19.9 mmol) of N-Boc-L-tyrosine methyl ester, and 6.26 g (23.9 mmol) oftriphenylphosphine in 150 mL of toluene at 45° C. was added dropwise asolution of 3.81 g (21.9 mmol) of DEAD in 50 mL of toluene. Theresulting clear solution was stirred at 20° C. for 8 hr, concentrated,and the residue re-dissolved into Et₂O (200 mL). To this was added 75 mLof 1 N NaOH solution. The mixture was rapidly stirred for 30 min untilphenol no longer present by TLC. The aqueous phase was extracted withEtOAc and the combined organics were dried (MgSO₄) and concentrated. Thecrude tan-colored solid lo was purified by silica gel chromatography(CH₂Cl₂/Et₂O, 12/1 to 8/1) to give an impure product. A second columneluting with CH₂Cl₂/hexane (4/1), CH₂Cl₂, and CH₂Cl₂/Et₂O (10/1) gave5.5 g (57% yield ) of a clear yellow oil. To this oil in 150 mL of THFwas added dropwise 13.7 mL of 1.0 M LiOH in H₂O solution. To this wasadded an additional 75 mL of THF and 5 mL of MeOH to give a clearsolution. The solution was stirred at 20° C. and the progress of thereaction was monitored by TLC (CHCl₃/MeOH, 9/1). The THF was removed atreduced pressure and the aqueous phase extracted with EtOAc/1.0 N HCl.The organics were washed with H₂O, dried over MgSO₄, concentrated, andthe resulting crude oil was purified by silica gel chromatography(EtOAc/hexanes, 1/1 to 8/1 gradient) to give 3.22 g (61%) of a foam. Tothis foam in 15 mL of dioxane was added dropwise 15 mL of 4.0 N HCl indioxane solution at 20° C. Stirred the mixture for 4 hr producing awhite solid precipitate. The solids were filtered washing with Et₂O,then dissolved into H₂O and the pH adjusted down to ˜pH 5 with thedropwise addition of 1.0 N NaOH solution. The resulting whiteprecipitate was collected by filtration and dried in a vacuum oven at60° C. overnight to yield 1.72 g of Intermediate 45 as a white solid.

Intermediate 46:(2S)-2-amino-3-(4-{2-[2-(4-fluorophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)propanoicacid

DEAD (1.26 mL, 8.16 mmol) was added dropwise to a solution of 2.14 g(8.16 mmol) of triphenylphosphine in 16 mL of THF at 0° C. This solutionwas then added to a mixture of 2.41 g (8.16 mmol) of N-(Boc)-L-Tyrosinemethyl ester (see, e.g., A. Kolodziejczyl, et al., J. Org. Chem., 46(9),pp 1944-1946 (1981)) and Intermediate 9 in 16 mL of THF at 0° C. Thesolution was stirred at 20° C. for 20 h and concentrated to an oil. Thecrude material was purified by silica gel chromatography (4:1hexanes:EtOAc) to yield 2.78 grams (69% yield) of the protected aminoacid Intermediate. Deprotection was achieved as follows: Esterhydrolysis—To a solution of 2.77 g (5.58 mmol) of the above ester in 45mL of THF and 15 mL of H₂O at 0° C. was added 8.5 mL (8.5 mmol) of 1.0 Maqueous LiOH solution. After 2 h at 20° C., EtOAc was added and themixture was acidified with 0.1 N HCl. The aqueous was extracted withEtOAc and the organics were dried (MgSO₄) and concentrated to give awhite glass-like solid (2.67 g). Boc Deprotection—The solid from theester hydrolysis above (2.64 g, 5.47 mmol) was taken into 60 mL CH₂Cl₂and treated with 30 mL of TFA with stirring for 1 h. The solution wasconcentrated, the residue was dissolved into ˜400 mL of H₂O, and the pHwas adjusted to is ˜pH 7 with aqueous 1.0 N NaOH solution. Thesuspension was filtered and the collected solids were dried for 48 h at70° C. under vacuum to yield 1.61 g (77% yield for deprotection, 53%overall yield) of Intermediate 46 as a fluffy beige-colored solid: ¹HNMR (DMSO-d₆, 300 MHz) δ7.93 (dd, 2H, J=8.7, 5.4), 7.3 (t, 2H, J=8.7),7.12 (d, 2H, J=8.0), 6.83 (d, 2H, J=8.2), 4.15 (t, 2H, J=6.5), 3.02 (dd,1H, J=14.2, 4.3), 2.89 (t, 2H, J=6.5), 2.76 (dd, 1H, J=8.2), 2.34 (s,3H); low resolution MS (ES+)m/e 384.9 (MH⁺).

Intermediates 47-51 were prepared analogous to the method describedabove for the preparation of Intermediate 46

Intermediate 47:(2S)-2-amino-3{4-[2(5-methyl-2-phenyl-1,3-thiazol-4-yl)ethoxy]phenyl}propanoicacid

Intermediate 47 was prepared from 2.41 g of N-(Boc)-L-Tyrosine methylester and 1.79 g of Intermediate 10 to yield 1.61 g (51% overall yield)of the title compound as a solid: ¹H NMR (DMSO-d₆, 400 MHz) δ7.82 (d,2H, J=7.5), 7.42 (m, 3H), 7.12 (d, 2H, J=8.2), 6.82 (d, 2H, J=8.4), 4.23(t, 2H, J=6.6), 3.1 (t, 2H, J=6.6), 2.83 (dd, 1H, J=14.1, 3.7), 2.53 (s,3H), second proton of methylene assumed under H₂O peak; low resolutionMS (ES+)m/e 383.1 (MH⁺);

Intermediate 48:(2S)-2-amino-3-(4-{2-[2-(4-fluorophenyl)-5-methyl-1,3-thiazol-4-yl]ethoxy}phenyl)propanoicacid

Intermediate 48 was prepared from 224 mg of N-(Boc)-L-Tyrosine methylester and 180 mg of Intermediate 11 to yield 149 mg (51% overall yield)of the title compound as a solid: ¹H NMR (DMSO-d₆, 400 MHz) δ7.82 (dd,2H, J=8.6, 5.5), 7.23 (t, 2H, J=8.7), 7.08 (d, 2H, J=8.4), 6.8 (d, 2H,J=8.5), 4.56 (br s, 1H), 4.19 (t, 2H, J=6.5), 3.56 (m, 1H), 3.03 (t, 2H,J=6.6), 2.95 (m, 1H), 2.79 (dd, 1H, J=14.5, 7.5), 2.37 (s, 3H); lowresolution MS (ES+)m/e 400.9 (MH⁺).

Intermediate 49:(2S)-2-amino-3-(4-{2-[2-methoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)propanoicacid

Intermediate 49 was prepared from 735 mg of N-(Boc)-L-Tyrosine methylester and 580 mg of Intermediate 12 to yield 220 mg (22% overall yield)of the title compound as a solid. ¹H NMR (DMSO-d₆, 400 MHz) δ8.16 (d,2H, J=8.2), 7.92 (d, 2H, J=8.4), 7.21 (d, 2H, J=8.5), 6.93 (d, 2H,J=8.5), 4.25 (t, 2H), J=6.5), 3.1 (dd, 1H), J=14.4, 4.8), 3.0 (t, 2H,J=6.5) 2.76 (dd, 1H, J=14.4, 7.9), 2.46 (s, 3H); low resolution MS(ES+)m/e 434.9 (MH⁺).

Intermediate 50:(2S)-2-amino-3-[4-(2-{5-methyl-2-[4-(trifluoromethyl)phenyl]-1,3oxazol-4-yl}ethoxy)phenyl]propanoicacid

Intermediate 50 was prepared from 185 mg of N-(Boc)-L-Tyrosine methylester and 170 mg of Intermediate 13 to yield 130 mg (48% overall yield)of the title compound as a solid: ¹H NMR (DMSO-d₆, 400 MHz) δ8.16 (d,2H, J=8.2), 7.92 (d, 2H, J=8.4), 7.21 (d, 2H, J=8.5), 6.93 (d, 2H,J=8.5), 4.25 (t, 2H, J=6.5), 3.1 (dd, 1H, J=14.4, 4.8), 3.0 (t, 2H,J=6.5), 2.76 (dd, 1H, J=14.4, 7.9), 2.46 (s, 3H); low resolution MS(ES+)m/e 434.9 (MH⁺).

Intermediate 51:(2S)-2-amino-3-(4-{2-[2-(4-isopropoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)propanoicacid

Intermediate 51 was prepared from 598 mg of N-(Boc)-L-Tyrosine methylester and 530 mg of Intermediate 14 to yield 540 mg (63% overall yield)of the title compound as a solid. ¹H NMR (DMSO-d₆, 400 MHz) δ7.77 (d,2H, J=8.7), 7.12 (d, 2H, J=8.6), 6.9 (d, 2H, J=8.9), 6.82 (d, 2H,J=8.5), 4.65 (hept, 1H, J=6.0), 4.13 (t, 2H, J=6.6), 3.0 (dd, 1H,J=14.4, 4.5), 2.85 (t, 2H, J=6.4), 2.76 (dd, 1H, J=14.4, 8.0), 2.31 (s,3H), 1.25 (d, 6H, J=6.0); low resolution MS (ES+)m/e 425.2 (MH⁺).

Intermediate 52:(2S)-2-amino-3-{4-[2(5-ethyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

To a mixture of 640 mg (2.95 mmol, 1.1 eq.) of alcohol intermediate 8B,790 mg (2.67 mmol, 1.0 eq.) of N-(Boc)-L-Tyrosine methyl ester, and 773mg (2.95 mmol, 1.1 eq.) of triphenylphosphine in 15 mL of anhydroustoluene at 50° C. was added 702 mg (3.47 mmol, 1.3 eq) of DIAD as asolution in 10 mL of toluene. Stirred 2.5 hr at 50° C. Cooled,concentrated, purified by loading directly onto a silica gel column.Elution with EtOAc/Hexanes (1/20 to 1/1) gave 1.15 grams (87% yield) ofBOC-protected intermediate methyl ester of sufficient purity to carryforward into the following deprotection reactions [¹H NMR (DMSO-d₆, 300MHz) δ8.07-8.03 (m, 2H), 7.47 (m, 3H), 7.03 (d, 2H, J=8.5), 6.85 (d, 2H,J=8.5), 4.58-4.51 (m, 1H), 4.26 (t, 2H, J=6.5), 3.72 (s, 3H), 3.06-3.0(m, 4H), 2.78 (q, 2H, J=7.5),,1.43 (s, 9H), 1.34 (t, 3H, J=7.6)];Deprotections: To a THF/H₂O (15 mL/5 mL) solution of 900 mg of the aboveprotected amino acid at 0° C. was added 2.64 mL of a 1.0 M LiOH in watersolution. Stirred 2.5 hrs. Diluted the mixture with 30 mL of EtOAc andthe pH was adjusted downward to ˜6 by the addition of 0.1 M HClsolution. The aqueous was extracted with EtOAc. The organics were dried(MgSO₄) and concentrated, then taken into DCM (15 mL) at 0° C. andtreated with 7.5 mL of TFA. The solution was concentrated after 1 hr,then concentrated several times from DCM to yield 1.4 g of crudeintermediate 52 (TFA salt). This solid was stirred with 50 mL of Et₂Ofor 30 min. The solids were collected via filtration and dried undervacuum for 12 h to yield 740 mg (67%) of the title compound as an offwhite solid: ¹H NMR (DMSO-d₆, 300 MHz) δ8.18 (br s, 2H), 7.93-7.90 (m,2H), 7.51-7.48 (m, 3H), 7.15 (d, 2H, J=8.5), 6.89 (d, 2H, J=8.4), 4.18(t, 2H, J=7.5), 4.11 (m, 1H), 3.01-2.99 (m, 2H), 2.95-2.95 (m, 2H), 2.75(q, 2H, J=7.5), 1.23 (t, 3H, J=7.5); low resolution MS (ES⁺)m/e 381.07(MH⁺).

Intermediate 53:(2S)-2-amino-3-{(4-[2-2-phenyl-5-propyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

Amino acid Intermediate 53 was prepared as described for the preparationof Intermediate 46. From 460 mg of N-(Boc)-L-Tyrosine methyl ester and360 mg of Intermediate 8C was prepared 410 mg (67% overall yield) of thetitle compound as a solid: ¹H NMR (DMSO-d₆, 300 MHz) δ7.90-7.87 (m, 2H),7.48-7.46 (m, 3H), 7.13 (d, 2H, J=8.4), 6.85 (d, 2H, J=8.4), 4.17 (t,2H, J=6.3), 4.0 (t, 1H, J=6.3), 2.99 (t, 1H, J=6.3), 2.92 (t, 1H,J=6.3), 2.69 (t, 2H, J=7.2), 1.66 (q, 2H, J=7.5), 0.93 (t, 3H, J=7.2);low resolution MS (ES⁺)m/e 395.09 (MH⁺); TLC R_(f)=0.24 (10/1,DCM/MeOH).

Intermediate 54:(2S)-2-amino-3-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenyl}propanoicacid

Amino acid Intermediate 54 was prepared as described for the preparationof Intermediate 46. From 187 mg of N-(Boc)-L-Tyrosine methyl ester and120 mg of Intermediate 8D (with DIAD replacing DEAD) was prepared 116 mg(53% overall yield) of the title compound as a solid. ¹H NMR (DMSO-d₆,300 MHz) δ7.89-7.85 (m, 2H), 7.43-7.36 (m, 3H), 7.12 (d, 2H, J=8.5), 6.9(d, 2H, J=8.5), 4.9 (s, 2H), 3.63 (m, 1H), 3.0 (dd, 1H, J=14.4, 4.5),2.85 (dd, 1H, J=14.4, 8.1), 2.37 (s, 3H); low resolution MS (ES+)m/e353.07 (MH⁺).

Intermediate 55:(2S)-2-amino-3-{4-[3-(5-methyl-2-phenyl-1,3-oxazol-4-yl)propoxy]phenyl}propanoicacid

Amino acid Intermediate 55 was prepared as described for the preparationof Intermediate 46. From 503 mg of N-(Boc)-L-Tyrosine methyl ester and370 mg of Intermediate 8E to yield 443 mg (68% overall yield) of thetitle compound as a solid. ¹H NMR (DMSO-d₆, 300 MHz) δ7.90-7.86 (m, 2H),7.52-7.44 (m, 3H), 7.14 (d, 2H, J=8.5), 6.86 (d, 2H, J=8.4), 3.94 (t,2H, J=6.2), 3.75 (m, 1H), 3.03 (dd, 1H, J=14.3, 5.1), 2.90 (dd, 1H,J=14.3, 7.2), 2.59 (t, 2H, J=7.3), 2.27 (s, 3H), 2.0 (m, 2H); TLCR_(f)=0.22 (10/1, DCM/MeOH); low resolution MS (ES+)m/e 381.12 (MH⁺).

Intermediate 56:(2S)-2-amino-3-(4-{2-[5ethyl-2-(4-fluorophenyl)-1,3-thiazol-4-yl]ethoxy}phenyl)propanoicacid

Intermediate 56 was prepared as described above for the preparation ofintermediate 52. From 534 mg of N-(Boc)-L-Tyrosine methyl ester and 500mg of Intermediate 11B was prepared 900 mg of BOC-protected intermediatemethyl ester (94% yield; ¹H NMR (CDCl₃, 300 MHz) δ7.9 (dd, 2H, 8.7,5.2), 7.13 (t, 2H, J=8.6), 7.04 (d, 2H, J=8.5), 6.85 (d, 2H, J=8.6),4.97 (d, 1H, J=7.9), 4.55 (m, 1H), 4.32 (t, 2H, J=6.8), 3.73 (s, 3H),3.21 (t, 2H, J=6.7), 3.10-3.02 (m, 2H), 2.89 (q, 2H, J=7.5), 1.44 (s,9H), 1.36 (t, 3H, J=7.5); From 850 mg of protected intermediate wasprepared 900 mg of intermediate 56 as a solid. ¹H NMR (DMSO-d₆, 300 MHz)δ8.0 (br s, 2H), 7.91-7.87 (m, 2H), 7.30 (dt, 2H, J=8.8, 2.1), 7.14 (d,2H, J=8.6), 6.90 (d, 2H, J=8.6), 4.27 (t, 2H, J=6.5), 4.12 (m, 1H), 3.11(t, 2H, J=6.5), 3.0 (m, 2H), 2.86 (q, 2H, J=7.5), 1.26 (t, 3H, J=7.5);low resolution MS (ES+)m/e 414.85 (MH⁺).

Intermediate 57:(2S)-2-amino-3-{4-[2-(5-ethyl-2-phenyl-1,3-thiazol-4-yl)ethoxy]phenyl}propanoicacid

Intermediate 57 was prepared as described above for the preparation ofintermediate 52. From 575 mg of N-(Boc)-L-Tyrosine methyl ester and 500mg of Intermediate 9B was prepared 940 mg of BOC-protected intermediatemethyl ester (94% yield; ¹H NMR (DMSO-d₆, 300 MHz) δ7.93 (m, 2H),7.47-7.41 (m, 3H), 7.04 (d, 2H, J=8.4), 6.86 (d, 2H, J=8.6), 4.96 (d,1H, J=4.56 (m, 1H), 4.34 (t, 2H, J=6.8), 3.73 (s, 3H), 3.23 (t, 2H,J=6.9), 3.04 (m, 2H), 2.90 (q, 2H, J=7.5), 1.44 (s, 9H), 1.37 (t, 3H,J=7.5)); From 900 mg of protected intermediate was prepared 900 mg ofintermediate 57 as a solid. ¹H NMR (DMSO-d₆, 300 MHz) δ8.16 (br s, 2H),7.85 (m, 2H), 7.5-7.43 (m, 3H), 7.14 (d, 2H, J=8.6), 6.90 (d, 2H,J=8.6), 4.27 (t, 2H, J=6.5), 4.12 (m, 1H), 3.12 (t, 2H, J=6.5), 3.0 (m,2H), 2.86 (q, 2H, J=7.5), 1.26 (t, 3H, J=7.5).

Intermediate 58:(2S)-2-amino-3-(4-{2-[5-ethyl-2-(4-fluorophenyl)-1,3-oxazol-4-yl]ethoxy}phenyl)propanoicacid

Intermediate 58 was prepared as described above for the preparation ofintermediate 52. From 230 mg of N-(Boc)-L-Tyrosine methyl ester and 200mg of Intermediate 10B was prepared 350 mg of BOC-protected intermediatemethyl ester (88% yield; ¹H NMR (DMSO-d₆, 300 MHz) δ8.07-8.01 (m, 2H),7.15 (t, 2H, J=8.7), 7.04 (d, 2H, J=8.5), 6.84 (d, 2H, J=8.5), 4.50 (m,1H), 4.24 (t, 2H, J=6.5), 3.72 (s, 3H), 3.04-2.99 (m, 2H), 2.77 (q, 2H,J=7.5), 1.44 (s, 9H), 1.33 (t, 3H, J=7.5); From 340 mg of BOC-protectedester intermediate was prepared 350 mg of intermediate 58 as a crudeoff-white colored solid. ¹H NMR (DMSO-d₆, 400 MHz) δ8.13 (br s, 2H),7.91 (dd, 2H, J=8.8, 5.3), 7.3 (t, 2H, J=8.9), 7.10 (d, 2H, J=8.6), 6.85(d, 2H, J=8.4), 4.13 (t, 2H, J=6.4), 4.08 (m, 1H), 2.98-2.95 (m, 2H),2.88 (t, 2H, J=6.5), 2.70 (q, 2H, J=7.4), 1.19 (t, 3H, J=7.5); lowresolution MS (ES+)m/e 399.13 (MH⁺).

Intermediate 59:(2S)-2-amino-3(4-{3-[5-ethyl-244-fluorophenyl)-1,3-oxazol-4-yl]propoxy}phenyl)propanoicacid

Intermediate 59 was prepared as described above for the preparation ofintermediate 52. From 370 mg of N-(Boc)-L-Tyrosine methyl ester and 310mg of Intermediate 10C was prepared 575 mg of BOC-protected intermediatemethyl ester (87% yield; ¹H NMR (CDCl₃, 400 MHz) δ7.95 (dd, 2H, J=8.6,5.4), 7.09 (t, 2H, J=8.7), 6.99 (d, 2H, J=8.4), 6.79 (d, 2H, J=8.5),4.50 (m, 1H), 3.92 (t, 2H, J=7.1), 3.68 (s, 3H), 3.05-2.93 (m, 2H),2.69-2.59 (m, 2H), 2.16-2.08 (m, 2H), 1.39 (s, 9H), 1.17 (t, 3H, J=7.6);From 562 mg of BOC-protected ester intermediate was prepared the crudeTFA salt of intermediate 59 as a solid (87%); ¹H NMR (DMSO-d₆, 400.MHz)δ7.97-7.9 (m, 2H), 7.33 (t, 2H, J=8.8), 7.14 (d, 2H, J=8.3), 6.88 (d,2H, J=8.1), 3.97 (m, 3H), 3.25-3.01 (m, 2H), 2.68-2.60 (m, 4H),2.04-1.99 (m, 2H), 1.16 (t, 3H, J=7.4); low resolution MS (ES+)m/e413.18 (MH⁺).

Intermediate 60:(2S)-2-amino-3-{4-[3-(5-ethyl-2-phenyl-1,3-oxazol-4-yl)propoxy]phenyl}propanoicacid

Intermediate 60 was prepared as described above for the preparation ofintermediate 52. From 266 mg of N-(Boc)-L-Tyrosine methyl ester and 208mg of Intermediate 8F was prepared 360 mg of BOC-protected intermediatemethyl ester (79% yield; ¹H NMR (CDCl₃, 300 MHz) δ8.06-8.03 (m, 2H),7.46-7.44 (m, 3H), 7.04 (d, 2H, J=8.4), 6.85 (d, 2H, J=8.4), 4.97 (d,1H, J=7.6), 4.57 (m, 1H), 3.99 (t, 2H, J=6.0), 3.74 (s, 3H), 3.05 (m,2H), 2.77-2.65 (m, 4H), 2.19 (t, 2H, J=6.6), 1.45 (s, 9H), 1.24 (t, 3H,J=7.5); From 352 mg of BOC-protected ester intermediate was prepared thecrude TFA salt of intermediate 60. The TFA salt was suspended into waterand the pH adjusted to ˜7.0 with 10% NaOH. The resulting solids werefiltered and dried to yield intermediate 60; ¹H NMR (DMSO-d₆, 400 MHz)δ7.88-7.85 (m, 2H), 7.48-7.43 (m, 3H), 7.11 (d, 2H, J=8.5), 6.82 (d, 2H,J=8.5), 3.92 (t, 2H, J=6.2), 3.55 (m, 1H), 3.0 (dd, 1H, J=14.3, 4.8),2.8 (dd, 1H, J=14.3, 7.7), 2.67-2.56 (m, 4H), 2.02-1.96 (m, 2H), 1.13(t, 3H, J=7.4); low resolution MS (ES+)m/e 392.9 (MH⁺); TLC R_(f)=0.44(4/1, DCM/MeOH).

Intermediate 61:(2S)-2-amino-3-{4-[(5-ethyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenyl}propanoicacid

Intermediate 61 was prepared as described above for the preparation ofintermediate 52. From 465 mg of N-(Boc)-L-Tyrosine methyl ester and 320mg of Intermediate 8G was prepared 520 mg of BOC-protected intermediatemethyl ester (69% yield; ¹H NMR (CDCl₃, 300 MHz) δ8.09-8.06 (m, 2H),7.47-7.46 (m, 3H), 7.08 (d, 2H, J=8.7), 6.97 (d, 2H, J=8.7), 5.02 (s,2H), 5.01 (s, 1H), 4.59-4.55 (m, 1H), 3.74 (s, 3H), 3.08-3.02 (m, 2H),2.83 (q, 2H, J=7.5), 1.45 (s, 9H), 1.32 (t, 3H, J=7.5); From 510 mg ofBOC-protected ester intermediate was prepared the crude TFA salt ofintermediate 61. The TFA salt was suspended into water and the pHadjusted to ˜7.0 with 10% NaOH. The resulting solids were filtered anddried to yield 315 mg of intermediate 61; ¹H NMR (DMSO-d₆, 300 MHz)δ7.96-7.94 (m, 2H), 7.52-7.51 (m, 3H), 7.18 (d, 2H, J=8.4), 6.95 (d, 2H,J=8.4), 4.97 (s, 3H), 3.10-3.05 (m, 1H), 2.86-2.79 (m, 4H), 1.22 (t, 3H,J=7.5); low resolution MS (ES+)m/e 366.86 (MH⁺); TLC R_(f)=0.52 (4/1,DCM/MeOH).

Intermediate 62:(2S)-2-amino-3-{4-[(5-ethyl-2-phenyl-1,3-thiazol-4-yl)methoxy]phenyl}propanoicacid

Intermediate 62 was prepared as described above for the preparation ofintermediate 52. From 3.27 g of N-(Boc)-L-Tyrosine methyl ester and 2.43g of Intermediate 9C was prepared 5.07 g of BOC-protected intermediatemethyl ester (92% yield; ¹H NMR (CDCl₃, 300 MHz) δ7.89-7.86 (m, 2H),7.42-7.38 (m, 3H), 7.01 (d, 2H, J=6.3), 6.94 (d, 2H, J=6.3), 5.11 (s,2H), 4.94 (d, 1H, J=6.0), 4.53-4.50 (m, 1H), 3.68 (s, 3H), 3.02-2.98 (m,2H), 2.90 (q, 2H, J=5.7), 1.39 (s, 9H), 1.30 (t, 3H, J=5.7); From 5.05 gof BOC-protected ester intermediate was prepared the crude TFA salt ofintermediate 62 as in example 52. The TFA salt was suspended into waterand the pH adjusted to ˜7.0 with 10% NaOH. The resulting solids werefiltered and dried to yield 4.28 g of intermediate 62; ¹H NMR (DMSO-d₆,400 MHz) δ7.85-7.83 (m, 2H), 7.45-7.43 (m, 3H), 7.16-7.14 (m, 2H),6.96-6.94 (m, 2H), 5.07 (s, 2H), 3.53 (s, 2H), 3.05-3.02 (m, 1H),2.91-2.81(m, 4H), 1.21 (t, 3H, J=7.4); low resolution MS (ES+)m/e 382.94(MH⁺); TLC R_(f)=0.33 (4/1, DCM/MeOH).

Intermediate 63:(2S)-2-amino-3-(4-{[5-ethyl-2-(4-fluorophenyl)-1,3-oxazol4-yl]methoxy}phenyl)propanoicacid

Intermediate 63 was prepared as described above for the preparation ofintermediate 52. From 962 mg of N-(Boc)-L-Tyrosine methyl ester and 720mg of Intermediate 10D was prepared 1.32 g of BOC-protected intermediatemethyl ester (81% yield; ¹H NMR (CDCl₃, 300 MHz) δ8.07-8.03 (m, 2H),7.19-7.13 (m, 2H), 7.08 (d, 2H, J=8.4), 6.97 (d, 2H, J=8.4), 4.99-4.97(m, 3H), 4.58-4.57 (m, 1H), 3.74 (s, 3H), 3.09-3.03 (m, 2H), 2.82 (q,2H. J=7.5), 1.59 (s, 9H), 1.30 (t, 3H, J=7.5); From 1.31 g ofBOC-protected ester intermediate was prepared the crude TFA salt ofintermediate 63. The TFA salt was suspended into water and the pHadjusted to ˜7.0 with 10% NaOH. The resulting solids were filtered anddried to yield 1.01 g of the title compound; ¹H NMR (DMSO-d₆, 300 MHz)δ8.01-7.97 (m, 2H), 7.36 (t, 2H, J=9.0), 7.18 (d, 2H, J=8.4), 6.96 (d,2H, J=8.4), 4.97 (s, 2H), 3.53-3.51 (m, 2H), 3.09-3.04 (m, 2H), 2.84 (q,2H, J=7.5), 1.22 (t, 3H, J=7.5); low resolution MS (ES+)m/e 384.87(MH⁺); TLC R_(f)=0.44 (4/1, DCM/MeOH).

Example 1(2S)-2{[(Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

A suspension of 3.0 g (8.2 mmol) of Intermediate 45 and 1.86 g (11.5mmol) of benzoylacetone in 26 mL of MeOH and 6 mL oftrimethylorthoformate was refluxed for 16 h with dissolution occurringsometime after 4 hrs. The solution was cooled, concentrated, and theresulting crude products were purified by silica gel chromatographyeluting with 1% to 100% MeOH in CH₂Cl₂. Column fractions homogeneous byTLC were combined and concentrated to give 1.8 g (43% yield) of Example1 as a tan-colored solid: TLC (EtOAc/MeOH (7:3): R_(f)=0.19; ¹H NMR(DMSO-d₆, 400 MHz) δ11.40 (d, 1H, J=8.89), 7.88 (d, 2H, J=7.86), 7.77(d, 2H, J=7.35), 7.46 (m, 3H), 7.39 (m, 3H), 7.10 (d, 2H, J=8.55), 6.80(d, 2H, J=8.20), 5.78 (s, 1H), 4.14 (m, 3H), 3.10 (m, 1H), 2.87 (m, 2H),2.77 (m, 1H), 2.34 (s, 3H), 1.71 (s, 3H): low resolution MS (ES+) m/e511.1 (MH⁺): RP-HPLC (Vydac C-18, 25 cm×4.6 mm; 30-100% CH₃CN in H₂O)with 0.1% HCO₂H buffer: 30 minutes; 1 mL/min: t_(r)=18.14 min(t_(o)=1.43); Daicel AD(2) (25 cm×4.6 mm; 20% IPA in Hexane) with 0.1%TFA buffer: 15 minutes; 0.8 mL/min: t_(r)=6.87 min (t_(o)=1.43),99.9%ee.

Example 2(2S)-3-(4-{2-[2-(4-fluorophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoicacid

A mixture of 75 mg (0.2 mmol) of Intermediate 46, 45 mg (0.2 mmol) ofIntermediate 24, and 57 μL (0.41 mmol) of triethylamine in 0.5 mL oftrimethylorthoformate and 2.5 mL of MeOH was refluxed for 10 hrs. Thesolvents were evaporated under reduced pressure and the residue purifieddirectly by silica gel chromatography. Elution with 5%-20% MeOH inCH₂Cl₂ gave 30 mg (26% yield) of Example 2 as a solid (foam); TLC(DCM/MeOH, 4/1): R_(f)=0.58; ¹H NMR (DMSO-d₆, 300 MHz) δ11.59 (d, 1H,J=9.8), 8.03 (m, 4H), 7.81 (d, 2H, J=8.8), 7.38 (t, 2H, J=9.2), 7.19 (d,2H, J=8.8), 6.88 (d, 2H, J=8.8), 5.76 (s, 1H), 4.21 (t, 2H, J=6.6), 4.17(m, 1H), 3.20 (m, 1H), 2.96 (t, 2H, J=6.6), 2.82 (m, 1H), 2.39 (s, 3H),1.76 (s, 3H); low resolution MS (ES+)m/e 597.0 (MH⁺).

Example 3(2S)-3-(4-{2-[2-(4-isopropoxyphenyl)-5-methyl-1,3-oxazol4-yl]ethoxy}phenyl)-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoicacid

The title compound was prepared (as described above for the preparationof Example 2) from 75 mg (0.18 mmol) of Intermediate 51 and 41 mg (0.18mmol) of Intermediate 24 to yield 48 mg (43% yield) of Example 3: TLC(DCM/MeOH, 4/1): R_(f)=0.42; ¹H NMR (DMSO-d₆, 400 MHz) δ11.5 (d, 1H,J=8.9), 7.95 (d, 2H, J=7.2), 7.77 (d, 2H, J=8.7), 7.72 (d, 2H, J=8.2),7.1 (d, 2H, J=8.4), 6.97 (d, 2H, J=8.9), 6.79 (d, 2H, J=8.5), 5.58 (s,1H), 4.65 (m, 1H), 4.11 (t, 2H, J=6.5), 4.1 (m, 1H), 3.16 (dd, 1H,J=13.7, 3.6), 2.84 (t, 2H, J=6.5), 2.74 (dd, 1H, 13.7, 9.0), 2.28 (s,3H), 1.67 (s, 3H), 1.25 (d, 6H, J=6.0); low resolution MS (ES+)m/e 637.1(MH⁺);

Example 4(2S)-3-(4-{2-[2-4-methoxyphenyl)-5-methyl-1,3oxazol-4-yl]ethoxy}phenyl)-2-({(Z)-1-methyl-3-oxo-3-[4(trifluoromethyl)phenyl]-1-propenyl}amino)propanoicacid

The title compound was prepared (as described above for the preparationof Example 2) from 100 mg (0.25 mmol) of Intermediate 49 and 58 mg (0.25mmol) of Intermediate 24 to yield 66 mg (43% yield) of Example 4: TLC(DCM/MeOH, 4/1): R_(f)=0.48; ¹H NMR (DMSO-d₆, 400 MHz) δ11.5 (d, 1H,J=8.9), 7.95 (d, 2H, J=8.2), 7.80 (d, 2H, J=8.7), 7.72 (d, 2H, J=8.4),7.1 (d, 2H, J=8.4), 7.0 (d, 2H, J=8.9), 6.79 (d, 2H, J=8.5), 5.58 (s,1H), 4.11 (t, 2H, J=6.5), 4.1 (m, 1H), 3.78 (s, 3H), 3.15 (dd, 1H,J=13.6, 3.6), 2.84 (t, 2H, J=66), 2.75 (dd, 1H, 13.7, 9.0), 2.28 (s,3H), 1.67 (s, 3H); low resolution MS (ES+)m/e 609.0 (MH⁺);

Example 5(2S)-2-{[(Z)-1-ethyl-3-oxo-3-phenyl-1-propenyl]amino}-3-[4-(2-{5-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}ethoxy)phenyl]propanoicacid

The title compound was prepared (as described above for the preparationof Example 2) from 40 mg (0.092 mmol) of Intermediate 50 and 17 mg(0.092 mmol) of Intermediate 16 to yield 21 mg of Example 5: TLC(DCM/MeOH, 4/1): R_(f)=0.50; ¹H NMR (DMSO-d₆, 400 MHz) δ11.59 (d, 1H,J=9.8), 8.09 (d, 2H, J=9.0), 7.85 (d, 2H, J=8.8), 7.78 (m, 2H), 7.39 (m,3H), 7.12 (d, 2H, J=8.0), 6.80 (d, 2H, J=8.0), 5.54 (s, 1H), 4.15 (t,2H, J=6.6), 4.17 (m, 1H), 3.11 (m, 1H), 2.90 (t, 2H, J=6.6), 2.72 (m,1H), 2.33 (s, 3H), 1.98 (m, 2H), 0.9 (t, 3H, J=7.5); low resolution MS(ES+)m/e 593.1 (MH⁺).

Example 6(2S)-2-([(Z)-1-ethyl-3-(4-fluorophenyl)-3-oxo-1-propenyl]amino}-3-(4-{2-[2-(4-methoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)propanoicacid

The title compound was prepared (as described above for the preparationof Example 2) from 100 mg (0.25 mmol) of Intermediate 49 and 62 mg (0.32mmol) of Intermediate 32 to yield 90 mg of Example 6: TLC (DCM/MeOH,4/1): R_(f)=0.46; ¹H NMR (DMSO-d₆, 400 MHz) δ11.45 (d, 1H, J=9.6), 7.84(m, 4H), 7.19 (t, 2H, J=8.8), 7.10 (d, 2H, J=8.4), 7.01 (d, 2H, J=8.8),6.78 (d, 2H, J=8.4), 5.51 (s, 1H), 4.11 (t, 2H, J=6.8), 4.03 (m, 1H),3.11 (m, 1H), 2.84 (t, 2H, J=6.8), 2.71 (dd, 1H, J=14.0, 9.2), 2.31 (s,3H), 1.98 (m, 2H), 0.90 (t, 3H, J=7.2); low resolution MS (ES−)m/e 571.2(M-H).

Example 7(2S)-2-{[(Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]amino}-3-[4-(2-{5-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}ethoxy)phenyl]propanoicacid

The title compound was prepared (as described above for the preparationof Example 2) from 40 mg (0.092 mmol) of Intermediate 50 and 15 mg(0.092 mmol) of benzoylacetone to yield 32 mg of Example 7: TLC(DCM/MeOH, 4/1): R_(f)=0.48; ¹H NMR (DMSO-d₆, 300 MHz) δ11.49 (d, 1H,J=9.8), 8.17 (d, 2h, J=8.9), 7.9 (d, 2H, J=8.9), 7.85 (m, 2H), 7.44 (m,3H), 7.19 (d, 2H, J=8.8), 6.89 (d, 2H, J=8.8), 5.60 (s, 1H), 4.23 (t,2H, J=6.0), 4.16 (m, 1H), 3.21 (m, 2H), 2.99 (t, 2H, J=6.0), 2.82 (dd,1H, J=14.2, 9.8), 2.42 (s, 3H), 1.78 (s, 3H); low resolution MS (ES+)m/e579.0 (MH⁺).

Example 8(2S)-2-{[(Z)-1-ethyl-3-oxo-3-phenyl-1-propenyl]amino}-3-(4-{2-[2-(4-fluorophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)propanoicacid

The title compound was prepared (as described above for the preparationof Example 2) from 75 mg (0.195 mmol) of Intermediate 46 and 34 mg (0.2mmol) of Intermediate 16 to yield 32 mg of Example 8: TLC (DCM/MeOH,4/1): R_(f)=0.63; ¹H NMR (DMSO-d₆, 300 MHz) δ11.57 (d, 1H, J=9.6), 7.97(m, 2H), 7.86 (d, 1H, J=7.2), 7.42 (m, 5H), 7.18 (d, 2H, 8.4), 6.87 (d,2H, J=8.4), 5.61 (s, 1H), 4.20 (t, 2H, J=6.6), 4.14 (m, 1H), 3.22 (m,2H), 2.94 (t, 2H, J=6.6), 2.83 (dd, 1H, J=13.8, 9.3); low resolution MS(ES+)m/e 543 (MH⁺).

Example 9(2S)-2-{[(Z)-1-ethyl-3-(4-fluorophenyl)-3-oxo-1-propenyl]amino}-3-(4-{2-[2(4-fluorophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)propanoicacid

The title compound was prepared (as described above for the preparationof Example 2) from 500 mg (1.56 mmol) of Intermediate 46 and 315 mg(1.56 mmol) of Intermediate 32 to yield 412 mg of Example 9: TLC(DCM/MeOH, 4/1): R_(f)=0.53; ¹H NMR (DMSO-d₆, 300 MHz) δ11.53 (d, 1H,J=9.3), 7.99 (m, 2H), 7.95 (m, 2H), 7.39 (t, 2H, J=8.7), 7.26 (t, 2H,J=8.7), 7.17 (d, 2H, J=8.1), 6.86 (d, 2H, J=8.1), 5.60 (s, 1H), 4.20 (t,2H, J=6.6), 4.12 (m, 1H), 3.21 (m, 2H), 2.94 (t, 2H, J=6.6), 2.78 (dd,1H, J=13.8, 8.4), 2.38 (s, 3H), 2.05 (m, 2H), 0.96 (t, 3H, J=7.5); lowresolution MS (ES+)m/e 561.4 (MH⁺).

Example 10(2S)-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-{4-[2-(5-methyl-2-phenyl-1,3-thiazol-4-yl)ethoxy]phenyl}propanoicacid

The title compound was prepared (as described above for the preparationof Example 2) from 290 mg (0.76 mmol) of Intermediate 47 and 150 mg(0.76 mmol) of Intermediate 24 to yield 140 mg (31% yield) of Example10: TLC (DCM/MeOH, 4/1): R_(f)=0.47; ¹H NMR (DMSO-d₆, 300 MHz) δ11.52(d, 1H, J=8.9), 7.96 (d, 2H, J=8.1), 7.80 (m, 2H), 7.72 (d, 2H, J=8.4 ),7.42 (m, 3H), 7.10 (d, 2H, J=8.4), 6.80 (d, 2H, J=8.4), 5.61 (s, 1H),4.20 (t, 2H, J=6.6), 4.15 (m, 1H), 3.17 (m, 1H), 3.05 (t, 2H, J=6.5),2.77 (dd, 1H, J=13.6, 8.6), 2.41 (s, 3H), 1.69 (s, 3H); low resolutionMS (ES+)m/e 595.0 (MH⁺).

Example 11(2S)-2-{[(Z)-3-(4-fluorophenyl)-1-methyl-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

A solution of 100 mg (0.27 mmol) of Intermediate 45 and 49 mg (0.27mmol) of Intermediate 26 in 2.5 mL MeOH and 0.5 mL trimethylorthoformate was refluxed at 80° C. for 16 h. The reaction solution wasconcentrated and purified by flash silica gel chromatography usingEtOAc/MeOH 7/3 as eluent to afford 83 mg of Example 11: TLC (EtOAc/MeOH,7/3): R_(f)=0.28; ¹H NMR (DMSO- d₆) δ11.38 (d, 1H, J=7.00), 7.84 (m,4H), 7.45 (m, 3H), 7.16 (t, 2H, J=8.72), 7.09 (d, 2H, J=7.69), 6.77 (d,2H, J=7.69), 5.49 (s, 1H), 4.11 (m, 2H), 4.01(m, br, 1H), 3.13 (m, 1H),2.86 (m, 2H), 2.72 (s, br, 1H), 2.30 (s, 3H), 1.62 (s, 3H); lowresolution MS (ES) m/e 529 (MH⁺); RP-HPLC (Vydac C-18, 25 cm×4.6 mm;30-100% CH₃CN in H₂O) with 0.1% HCO₂H buffer: 30 minutes; 1 mL/min:t_(r)=20.10 min (t_(o)=1.53).

Example 12(2S)-2-{[(Z)-1-methyl-3-oxo-3-(2,3,4-trifluorophenyl)-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

A mixture of 680 mg (1.85 mmol) of Intermediate 45, 367 mg (1.85 mmol)of Intermediate 36, and 0.67 mL (3.7 mmol) of DIEA in 15 mL of MeOH wasrefluxed overnight (14 h). The solvent was evaporated under reducedpressure and the residue purified directly by silica gel chromatography.Elution with 5%-20% MeOH in CH₂Cl₂ gave 612 mg (58% yield) of the titlecompound as a solid: TLC (DCM/MeOH, 4/1): R_(f)=0.50; ¹H NMR (DMSO-d₆,300 MHz) δ11.35 (d, 1H, J=9.0), 7.87 (m, 2H), 7.48 (m, 4H), 7.3 (q, 1H,J=5.4), 7.10 (d, 2H, J=8.7), 6.78 (d, 2H, J=8.7), 5.25 (s, 1H), 4.18 (m,3H), 3.19 (m, 2H), 2.86 (t, 2H, J=6.3), 2.74 (dd, 1H, J=13.8, 9.0), 2.32(s, 3H), 1.64 (s, 3H); low resolution MS (ES+)m/e 564.9 (MH⁺);

Example 13(2S)-2-{[(Z)-1-methyl-3-(4-nitrophenyl)-3-oxo-1-propenyl]amino}-3-{4-[2-(5ethyl-2-phenyl-1,3oxazol-4-yl)ethoxy]phenyl}propanoicacid

The title compound was prepared (as described above for the preparationof Example 12) from 120 mg (0.33 mmol) of Intermediate 45 and 62 mg(0.33 mmol) of Intermediate 41 to yield 105 mg (58% yield) of Example13: TLC (DCM/MeOH, 4:1): R_(f)=0.60; ¹H NMR (DMSO-d₆, 300 MHz) δ11.66(d, 1H, J=9.0), 8.29 (d, 2H, J=8.4), 8.08 (d, 2H, J=8.4), 7.97 (m, 2H)7.56 (m, 3H), 7.19 (d, 2H, J=8.0), 6.88 (d, 2H, J=8.0), 5.72 (s, 1H),4.18 (m, 3H), 3.23 (m, 1H), 2.96 (t, 2H, J=6.2), 2.85 (dd, 1H, J=13.4,9.6), 2.39 (s, 3H), 1.79 (s, 3H); low resolution MS (ES+)m/e 556.4(MH⁺).

Example 14(2S)-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-{4-[2-(5-methyl-2-phenyl-1,3oxazol-4-yl)ethoxy]phenyl}propanoicacid

A solution of 676 mg (1.85 mmol) of Intermediate 45 and 510 mg (2.22mmol) of Intermediate 24 in 30 mL MeOH and 6 mL trimethyl orthoformatewith 4 A sieves (300 mg) was refluxed at 80° C. for 16 h. The reactionsolution was concentrated and purified by flash silica gel columnchromatography using DCM/MeOH 15/1 followed by DCM/MeOH 10/1 as eluentto afford 329 mg of Example 14: TLC (DCM/MeOH (9:1): R_(f)=0.26; ¹H NMR(DMSO-d₆, 300 MHz) δ11.59 (d, 1H, J=9.0), 8.03 (d, 2H, J=8.1), 7.95 (m,2H), 7.80 (d, 2H, J=8.1), 7.56 (m, 3H), 7.19 (d, 2H, J=8.4), 6.87 (d,2H, J=8.4), 5.66 (s, 1H), 4.18 (m, 3H), 3.23 (m, 2H), 2.95 (t, 2H,J=6.6), 2.82 (dd, 1H, J=13.8, 9.0), 2.39 (s, 3H), 1.75 (s, 3H); lowresolution MS (ES+)m/e 579 (MH⁺); RP-HPLC (Vydac C-18, 25 cm×4.6 mm;30-100% CH₃CN in H₂O) with 0.1% HCO₂H buffer: 30 minutes; 1 mL/min:t_(r)=21.47 min (t_(o)=1.53).

Example 15(2S)-2-{[(Z)-1-ethyl-3-(4-fluorophenyl)-3-oxo-1-propenyl]amino}-3-(4-{2-[2-(4-isopropoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)propanoicacid

The title compound was prepared (as described above for the preparationof Example 2) from 75 mg (0.177 mmol) of Intermediate 51 and 39 mg(0.194 mmol) of Intermediate 32 to yield 70 mg of Example 15: TLC(DCM/MeOH (4:1): R_(f)=0.55; ¹H NMR (DMSO-d₆, 300 MHz) δ11.53 (d, 1H,J=9.6), 7.89 (dd, 2H, J=8.8, 5.7), 7.85 (d, 2H, J=8.8), 7.26 (t, 2H,J=8.8), 7.18 (d, 2H, J=8.5), 7.05 (d, 2H, J=8.8), 6.86 (d, 2H, J=8.5),5.60 (s, 1H), 4.73 (hept, 1H, J=6.0), 4.19 (t, 2H, J=6.7), 4.13 (br s,1H), 3.19 (m, 1H), 2.92 (t, 2H, J=6.6), 2.80 (dd, 1H, J=14.0, 9.2), 2.36(s, 3H), 2.07 (m, 2H), 1.34 (d, 6H, J=6.0), 0.99 (t, 3H, J=7.5); lowresolution MS (ES+)m/e 601.1 (MH⁺).

Example 16(2S)-2-{[(Z)-1-methyl-3-oxo-3-(2,4,5-trifluorophenyl)-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

The title compound was prepared (as described above for the preparationof Example 12) from 677 mg (1.85 mmol) of Intermediate 45 and 366 mg(1.85 mmol) of Intermediate 38 to yield 482 mg (46% yield) of Example16. TLC (DCM/MeOH (4:1): R_(f)=0.55; ¹H NMR (DMSO-d₆, 300 MHz) δ11.39(d, 1H, J=8.9), 7.86 (m, 2H), 7.69-7.59 (m, 1H), 7.54-7.40 (m, 4H), 7.10(d, 2H, J=8.5), 6.79 (d, 2H, J=8.5), 5.3 (s, 1H), 4.12 (t, 2H, J=6.5),4.1 (m, 1H), 3.16 (m, 1H), 2.86 (t, 2H, J=6.5), 2.76 (dd, 1H, J=13.7,8.9), 2.3 (s, 3H), 1.64 (s, 3H): low resolution MS (ES+)m/e 565.1 (MH⁺).

Example 17(2S)-2-{[(Z)-1-ethyl-3-oxo-3-phenyl-1-propenyl]amino}-3-(4-{2-[2-(4-isopropoxyphenyl)-5-methyl-1,3oxazol-4-yl]ethoxy}phenyl)propanoicacid

The title compound was prepared (as described above for the preparationof Example 2) from 75 mg (0.177 mmol) of Intermediate 51 and 34 mg(0.194 mmol) of Intermediate 16 to yield 30 mg of Example 17: TLC(DCM/MeOH (4:1): R_(f)=0.63; ¹H NMR (DMSO-d₆, 400 MHz) δ11.49 (d, 1H,J=9.6), 7.77 (m, 4H), 7.37 (m, 3H), 7.10 (d, 2H, J=8.8), 6.97 (d, 2H,J=9.2), 6.79 (d, 2H, J=9.2), 5.54 (s, 1H), 4.66 (septuplet, 1H, J=6.0),4.12 (t, 2H, J=6.8), 4.04 (m, 1H), 3.35 (m, 1H), 3.11 (m, 1H), 2.84 (t,2H, J=6.8), 2.72 (dd, 1H, J=13.9, 9.2), 2.28 (s, 3H), 1.99 (m, 2H), 1.26(d, 6H, J=6.0), 0.91 (m 3H, J=7.6); low resolution MS (ES+)m/e 583.1(MH⁺).

Example 18(2S)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

The title compound was prepared (as described above for the preparationof Example 2) from 197 mg (0.41 mmol) of Intermediate 45 (as the TFAsalt) and 100 mg (0.41 mmol) of Intermediate 25 to yield 110 mg (45%yield) of Example 18: TLC (DCM/MeOH (4:1): R_(f)=0.60; ¹H NMR (DMSO-d₆,400 MHz) δ11.45 (d, 1H, J=9.2), 7.85 (m, 4H), 7.47 (m, 3H), 7.17 (t, 2H,J=8.8), 7.09 (d, 2H, J=8.4), 6.78 (d, 2H, J=8.4), 5.51 (s, 1H), 4.12 (t,2H, J=6.4), 4.02 (m, 1H), 3.10 (m, 2H), 2.86 (t, 2H, J=6.4), 2.71 (dd,1H, J=13.9, 9.2), 2.31 (s, 3H), 1.98 (s, 3H), 0.90 (t, 3H, J=7.6); lowresolution MS (ES+)m/e 593 (MH⁺).

Example 19(2S)-2-{[(Z)-1-methyl-3-(4-methylphenyl)-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

The title compound was prepared (as described above for the preparationof Example 2) from 790 mg (1.64 mmol) of Intermediate 45 (as the TFAsalt) and 0.29 g (1.64 mmol) of Intermediate 27 (with 660 μL of DCAreplacing Et₃N) to yield crude product contaminated with DCA). A secondsilica gel chromatography column eluting with 8:1 DCM:MeOH gave 70 mg ofExample 19 as a beige-colored solid: TLC (DCM/MeOH (4:1): R_(f)=0.58; ¹HNMR (DMSO-d₆, 400 MHz) δ11.43 (d, 1H, J=9.0), 7.96 (m, 2H), 7.74 (d, 2H,J=8.1), 7.54 (m, 3H), 7.24 (d, 2H, J=8.1), 7.18 (d, 2H, J=8.4), 6.87 (d,2H, J=8.4), 5.57 (s, 1H), 4.21 (t, 2H, J=6.6), 4.08 (m, 1H), 3.23 (m,2H), 2.95 (t, 2H, J=6.6), 2.80(dd, 1H, J=13.8, 9.0), 2.39 (s, 3H), 2.37(s, 3H), 1.71 (s, 3H); low resolution MS (ES+)m/e 525.2 (MH⁺).

Example 20(2S)-2-{[(Z)-1-ethyl-3-oxo-3-phenyl-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

The title compound was prepared (as described above for the preparationof Example 2) from 1.03 g (2.1 mmol) of Intermediate 45 (as the TFAsalt) and 740 mg (4.2 mmol) of Intermediate 16 to yield 500 mg ofExample 20 as a white solid: TLC (EtOAc/MeOH, 7/3): R_(f)=0.35; ¹H NMR(DMSO-d₆, 400 MHz) δ11.55 (d, 1H, J=9.6), 7.93 (d, 2H, J=7.8), 7.84 (d,2H, J=7.8), 7.57 (m, 3H), 7.52 (m, 3H), 7.18 (d, 2H, J=8.4), 6.87 (d,2H, J=8.4), 5.58 (s, 1H), 4.21 (t, 2H, J=6.6), 4.16 (m, 1H), 3.21 (m,1H), 2.95 (t, 2H, J=6.6), 2.80 (dd, 1H, J=13.5, 9.0), 2.42 (s, 3H), 2.08(m, 2H), 1.04 (t, 3H, J=7.8); low resolution MS (ES+)m/e 525 (MH⁺).

Example 21(2S)-3-(4-{2-[2-(4-fluorophenyl)-5-methyl-1,3-thiazol-4-yl]ethoxy}phenyl)-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoicacid

A solution of 120 mg (0.31 mmol) of Intermediate 48, 62 mg (0.31 mmol)of Intermediate 44, and 110 μL (2 equivalents) of DIEA in MeOH (3.5 mL)was refluxed for 10 hrs. The solvents were removed under reducedpressure and the crude products were purified by silica gelchromatography (gradient, 15/1 to 10/1 CH₂Cl₂/MeOH) to give 78 mg (46%yield) of Example 21 as a solid: TLC (DCM/MeOH (4:1): R_(f)=0.62; ¹H NMR(DMSO-d₆, 400 MHz) δ10.9 (br s, 1H), 7.9-7.83 (m, 4H), 7.6-7.43 (m, 3H),7.27 (t, 2H, J=8.8), 7.05 (d, 2H, J=8.4), 6.78 (d, 2H, J=8.4), 6.13 (s,1H), 4.2 (t, 2H, J=6.6), 4.08 (br s, 1H), 3.1 (m, 1H), 3.08 (t, 2H,J=6.7), 2.86 (dd, 1H, J=13.6, 7.7), 2.37 (s, 3H); low resolution MS(ES+)m/e 599.0 (MH⁺).

Example 22(2S)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1propenyl}amino)-3-(4-{2-[2-(4-fluorophenyl)-5-methyl-1,3-thiazol-4-yl]ethoxy}phenyl)propanoicacid

The title compound was prepared (as described above for the preparationof Example 2) from 75 mg (0.19 mmol) of Intermediate 48 and 46 mg (0.19mmol) of Intermediate 25 to yield 26 mg of Example 22: TLC (DCM/MeOH(4:1): R_(f)=0.58; ¹H NMR (DMSO-d₆, 400 MHz) δ11.59 (d, 1H, J=9.3), 7.97(d, 2H, J=8.1), 7.85 (m, 2H), 7.72 (d, 2H, J=8.4), 7.29 (m, 2H), 7.10(t, 2H, J=8.4), 6.79 (d, 2H, J=8.4), 5.60 (s, 1H), 4.20 (t, 2H, J=6.6),4.12 (m, 1H), 3.16 (m, 1H), 3.06 (t, 2H, J=6.6), 2.75 (dd, 1H, J=13.8,9.0), 2.38 (s, 3H), 2.02 (m, 2H), 0.92 (t, 3H, J=7.5); low resolution MS(ES+)m/e 627.0 (MH⁺).

Example 23(2S)-2-{[(Z)-1-butyl-3-oxo-3-phenyl-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

The title compound was prepared (as described above for the preparationof Example 2) from 1.0 g (2.05 mmol) of Intermediate 45 (as the TFAsalt) and 0.86 g (4.2 mmol) of Intermediate 18 to yield 290 mg (25%yield) of Example 23 as a solid: TLC (EtOAc/MeOH , 7/3): R_(f)=0.55; ¹HNMR (DMSO-d₆, 400 MHz) δ11.59 (d, 1H, J=9.7), 7.86 (m, 2H), 7.76 (m,2H), 7.48-7.34 (m, 6H), 7.10 (d, 2H, J=8.5), 7.10 (t, 2H, J=8.4), 6.8(d, 2H, J=8.6), 5.52 (s, 1H), 4.12 (t, 2H, J=6.5), 4.02 (m, 1H), 3.16(m, 1H), 2.86 (t, 2H, J=6.5), 2.75 (dd, ₁H, J=13.5, 9.5), 2.31 (s, 3H),1.9 (m, 2H), 1.3-1.1 (m, 4H), 0.73 (t, 3H, J=6.9); low resolution MS(ES+)m/e 553.2 (MH⁺).

Example 24(2S)-2-{[(Z)-3-(4-chlorophenyl)-1-methyl-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

The title compound was prepared (as described above for the preparationof Example 2) from 100 mg (0.27 mmol) of Intermediate 45 and 54 mg (0.27mmol) of Intermediate 28 to yield 76 mg of Example 24: TLC (DCM/MeOH(4:1): R_(f)=0.52; ¹H NMR (DMSO-d₆, 300 MHz) δ11.52 (d, 1H, J=9.6), 7.97(m, 2H), 7.87 (d, 2H, J=8.6), 7.55 (m, 5H), 7.18 (d, 2H, J=8.5), 6.86(d, 2H, J=8.5), 5.59 (s, 1H), 4.21 (t, 2H, J=6.1), 4.09 (m, 1H), 3.22(m, 1H), 2.96 (t, 2H, J=6.1), 2.78 (dd, ₁H, J=13.9, 9.4), 2.39 (s, 3H),1.73 (s, 3H).

Example 25(2S)-2-{[(Z)-1-methyl-3-(3-nitrophenyl)-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3oxazol-4-yl)ethoxy]phenyl}propanoicacid

The title compound was prepared (as described above for the preparationof Example 12) from 120 mg (0.25 mmol) of Intermediate 45 and 48 mg(0.25 mmol) of Intermediate 42 to yield 67 mg of Example 25: TLC(DCM/MeOH (4:1): R_(f)=0.52; ¹H NMR (DMSO-d₆, 400 MHz) δ11.52 (d, 1H,J=9.1), 8.52 (s, 1H), 8.24 (d, 1H, J=8.2), 8.21 (d, 2H, J=7.7), 7.87 (d,2H, J=7.7), 7.66 (t, 1H, J=7.9), 7.45 (m, 3H), 7.10 (d, 2H, J=8.2), 6.79(d, 2H, J=8.3), 5.74 (s, 1H), 4.13 (t, 2H, J=6.6), 4.07 (br s, 1H), 3.15(m, 1H), 2.87 (t, 2H, J=6.4), 2.75 (m, 1H), 2.31 (s, 3H), 1.68 (s, 3H).;low resolution MS (ES+)m/e 556.3 (MH⁺).

Example 26(2S)-2-({(Z)-3-[2-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-3-oxo-1-propenyl}amino)-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

The title compound was prepared (as described above for the preparationof Example 12) from 190 mg (0.52 mmol) of Intermediate 45 and 120 mg(0.52 mmol) of Intermediate 37 to yield 102 mg (35% yield) of Example26: ¹H NMR (DMSO-d₆, 400 MHz) δ11.36 (d, 1H, J=8.9), 7.9 (m, 3H), 7.77(t, 1H, J=6.9), 7.46 (m, 3H), 7.42 (m, 1H), 7.11 (d, 2H, J=8.5), 6.81(d, 2H, J=8.5), 5.22 (s, 1H), 4.14 (t, 2H, J=6.6), 4.1 (m, ₁H), 3.13 (m,1H), 2.87 (t, 2H, J=6.6), 2.78 (dd, 1H, J=13.7, 8.5), 2.31 (s, 3H), 1.68(s, 3H); low resolution MS (ES+)m e 597.4(MH⁺).

Example 27(2S)-2-{[(Z)-3-(4-isopropoxyphenyl)-1-methyl-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

The title compound was prepared (as described above for the preparationof Example 2) from 435 mg (0.91 mmol) of Intermediate 45 (as the TFAsalt) and 200 mg (0.91 mmol) of Intermediate 29 to yield 125 mg ofExample 27 as a beige glassy solid: TLC (DCM/MeOH (4:1): R_(f)=0.50; ¹HNMR (DMSO-d₆, 400 MHz) δ11.29 (d, 1H, J=8.8), 7.88 (m, 2H), 7.70 (d, 2H,8.8), 7.48 (m, 3H), 7.09 (d, 2H, J=8.0), 6.85 (d, 2H, J=8.8), 6.78 (d,2H, J=8.0), 5.46 (s, 1H), 4.62 (septuplet, 1H, J=6.4), 4.12 (t, 2H,J=6.4), 4.0 (m, 1H), 3.14 (m, 2H), 2.87 (t, 2H; J=6.4), 2.70 (dd, 1H,J=13.2, 9.6), 2.31 (s, 3H), 1.61 (s, 3H), 1.21 (d, 6H, J=6.4); lowresolution MS (ES+)m/e 569 (MH⁺).

Example 28(2S)-2-{[(Z)-3-(2-chlorophenyl)-1-methyl-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

The title compound was prepared (as described above for the preparationof Example 2) from 100 mg (0.27 mmol) of Intermediate 45 and 54 mg (0.27mmol) of Intermediate 29 to yield 44 mg of Example 27: TLC (DCM/MeOH(4:1): R_(f)=0.47; ¹H NMR (DMSO-d₆, 400 MHz) δ11.12 (d, 1H, J=9.0), 7.91(m, 2H), 7.44 (m, 3H), 7.39 (m, 1H), 7.33 (m, 3H), 7.17 (d, 2H, J=7.2),6.80 (d, 2H, J=7.2), 4.97 (s, 1H), 4.14 (m, 3H), 3.16 (m, 1H), 2.88 (m,2H), 2.77 (m, 1H), 2.32 (s, 3H), 1.61 (s, 3H); low resolution MS(ES−)m/e 545.0 (M-H).

Example 29(2S)-2-{[(Z)-3-(2-furyl)-1-methyl-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

The title compound was prepared (as described above for the preparationof Example 2) from 630 mg (1.31 mmol) of Intermediate 45 (as the TFAsalt) and 200 mg (1.31 mmol) of 1-(2-furyl)-1,3-butadione (purchasedfrom Acros Organics) to yield 230 mg (35% yield) of Example 29 as alight brown solid: TLC (DCM/MeOH (4:1): R_(f)=0.62; ¹H NMR (DMSO-d₆, 300MHz) δ11.07 (d, 1H, J=8.7), 7.88 (m, 2H), 7.69 (d, ₁H, J=1.0), 7.48 (m,3H), 7.09 (d, 2H, J=8.5), 6.86 (m, 3H), 6.52 (d, 1H, J=1.5), 5.33 (s,1H), 4.13 (t, 2H, J=6.6), 4.03 (m, 1H), 3.14 (m, 1H), 2.87 (t, 2H,J=6.6), 2.70 (dd, 1H, J=13.6, 9.0), 2.34 (s, 3H), 1.62 (s, 3H); lowresolution MS (ES+)m/e 501.2 (MH⁺).

Example 30(2S)-2-{[(Z)-1-methyl-3-oxo-3-(2-pyrazinyl)-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

The title compound was prepared (as described above for the preparationof Example 2) from 292 mg (0.61 mmol) of Intermediate 45 (as the TFAsalt) and 100 mg (0.61 mmol) of Intermediate 35 to yield 135 mg (43%) ofExample 30: TLC (DCM/MeOH (4:1): R_(f)=0.22; ¹H NMR (DMSO-d₆, 400 MHz)δ11.58 (d, 2H, J=8.8), 9.08(s, 1H), 8.68 (s, 1H), 8.60 (s, 1H), 7.87 (d,2H, J=7.6), 7.45 (m, 3H), 7.11 (d, 2H, J=8.0), 6.81 (d, 2H, J=8.0), 6.04(s, 1H), 4.13 (m, 3H), 3.17 (m, 1H), 2.87 (t, 2H, J=6.4), 2.78 (dd, 1H,J=13.2, 9.2), 2.31 (s, 3H), 1.71 (s, 3H); low resolution MS (ES−)m/e511.1 (M-H).

Example 31(2S)-2-{[(Z)-3-(2,4-difluorophenyl)-1-methyl-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

The title compound was prepared (as described above for the preparationof Example 12) from 120 mg (0.33 mmol) of Intermediate 45 and 59 mg(0.33 mmol) of Intermediate 39 to yield 63 mg (35% yield) of Example 31:TLC (DCM/MeOH (4:1): R_(f)=0.72; ¹H NMR (DMSO-d₆, 400 MHz) δ11.37 (d,1H, J=9.4), 7.87 (m, 2H), 7.72 (q, 1H, J=6.4), 7.43 (m, 3H), 7.14 (m,4H), 6.79 (d, 2H, J=8.8), 5.25 (s, 1H), 4.13 (m, 3H), 3.18 (m, 1H), 2.85(t, 2H, J=6.0), 2.77 (dd, 1H, J=14.0, 9.8), 2.29 (s, 3H), 1.62 (s, 3H) ;low resolution MS (ES−)m/e 545.1 (M-H).

Example 32(2S)-2-{[(Z)-1-methyl-3-oxo-3-(1,3-thiazol-2-yl)-1-propenyl]amino}-3-{[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

The title compound was prepared (as described above for the preparationof Example 12) from 200 mg (0.43 mmol) of Intermediate 45 (as the TFAsalt) and 65 mg (0.43 mmol) of Intermediate 43 to yield 202 mg of crudeproduct. This material was re-columned on silica gel eluting withDCM/MeOH (6/1 to 4/1 gradient) to yield 22 mg of Example 32.: TLC(DCM/MeOH, 4/1): R_(f)=0.42; 1H NMR (DMSO-d₆, 300 MHz) δ11.25 (d, 1H,J=9.0), 7.94 (m, 4H), 7.54 (m, 3H), 7.17 (d, 2H, J=8.4), 6.88 (d, 2H,J=8.4), 5.84 (s, 1H), 4.22 (t, 2H, J=6.6), 4.18 (m, 1H), 3.1 (dd, 1H,J=14.0, 4.0), 2.96 (t, 2H, J=6.6), 2.83 (dd, 1H, J=13.8, 9.0), 2.43 (s,3H), 1.76 (s, 3H); low resolution MS (ES+)m/e 518.1 (MH⁺).

Example 33

(2S)-2-{[(Z)-1-methyl-3-oxo-3-(3-thienyl)-1-propenyl]amino}-3-{4-[2-(5methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

The title compound was prepared (as described above for the preparationof Example 2) from 428 mg (0.89 mmol) of Intermediate 45 (as the TFAsalt) and 150 mg (0.89 mmol) of Intermediate 31 to yield 210 mg ofExample 33: TLC (DCM/MeOH, 4/1): R_(f)=0.60; ¹H NMR (DMSO-d₆, 400 MHz)δ11.8 (d, ₁H, J=9.2), 7.88 (m, 3H), 7.42 (m, 5H), 7.08 (d, 2H, J=8.4),6.78 (d, 2H, J=8.4), 5.39 (s, 1H), 4.12 (t, 2H, J=6.4), 4.01 (m, 1H),3.23 (m, 1H), 3.09 (m, 1H), 2.86 (t, 2H, J=6.4), 2.69 (dd, 1H, J=13.6,9.2), 2.31 (s, 3H), 1.60 (s, 3H); low resolution MS (ES+)m/e 517.1(MH⁺).

Example 34(2S)-2-{[(Z)-1-methyl-3-oxo-3-(2-pyridinyl)-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

The title compound was prepared (as described above for the preparationof Example 2) from 441 mg (0.92 mmol) of Intermediate 45 (as the TFAsalt) and 150 mg (0.92 mmol) of Intermediate 35 to yield 240 mg ofExample 34: TLC (DCM/MeOH, 4/1): R_(f)=0.46; ¹H NMR (DMSO-d₆, 400 MHz)δ11.49 (d, 1H, J=9.2), 8.52 (d, 1H, J=4.8), 7.90 (m, 4H), 7.47 (m, 4H),7.11 (d, 2H, J=8.4), 6.80 (d, 2H, J=8.4), 6.13 (s, 1H), 4.12 (m, 3H),3.16 (m, 2H), 2.87 (t, 2H, J=6.4), 2.77 (dd, 1H, J=13.6, 9.2), 2.34 (s,3H), 1.71 (s, 3H); low resolution MS (ES−)m/e 510.1 (M-H).

Example 35(2S)-2-{[(Z)-1-ethyl-3-(4-fluorophenyl)-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

The title compound was prepared (as described above for the preparationof Example 2) from 100 mg (0.27 mmol) of Intermediate 45 and 49 mg (0.27mmol) of Intermediate 32 to yield 83 mg of Example 35: TLC (EtOAc/MeOH(7:3): R_(f)=0.28; ¹H NMR (DMSO-d₆, 400 MHz) δ11.38 (d, 1H, J=7.00),7.84 (m. 4H), 7.45 (m, 3H), 7.16 (t, 2H, J=8.72), 7.09 (d, 2H, J=7.69),6.77 (d, 2H, J=7.69), 5.49 (s, 1H), 4.11 (m, 2H), 4.01(m, br, 1H), 3.13(m, 1H), 2.86 (m, 2H), 2.72 (s, br, 1H), 2.30 (s, 3H), 1.62 (s, 3H); lowresolution MS (ES+) m/e 529 (MH⁺); RP-HPLC (Vydac C-18, 25 cm×4.6 mm;30-100% CH₃CN in H₂O) with 0.1% HCO₂H buffer: 30 minutes; 1 mL/min:t_(r)=20.10 min (t_(o)=1.53).

Example 36(2S)-2-{[(Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-thiazol-4-yl)ethoxy]phenyl}propanoicacid

The title compound was prepared (as described above for the preparationof Example 2) from 0.5 g (1.31 mmol) of Intermediate 46 and 215 mg (1.31mmol) of benzoyl acetone and 260 μL (1.31 mmol) of dicycylohexylamine(replacing TEA) to yield a total of 245 mg of Example 36 as a dullyellow solid. TLC (EtOAc/MeOH (3:1): R_(f)=0.56; ¹H NMR (DMSO-d₆, 400MHz) δ11.4 (d, 1H, J=9.1), 7.81 (m, 2H), 7.75 (m, 2H), 7.42 (m, 3H),7.36 (m, 3H), 7.0 (d, 2H, J=8.4), 6.78 (d, 2H, J=8.6), 5.51 (s, 1H),4.55 (m, 1H), 4.20 (t, 2H, J=6.7), 4.0 (br s, 1H), 3.14-3.04 (m, 3H),2.7 (m, 1H), 2.38 (s, 3H), 1.68 (s, 3H) ; low resolution MS (ES+)m/e527.1 (MH⁺).

Example 37(2S)-2-{[(Z)-3-(2-fluorophenyl)-1-methyl-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

The title compound was prepared (as described above for the preparationof Example 2) from 100 mg (0.27 mmol) of Intermediate 45 and 58 mg (0.32mmol) of Intermediate 20 to yield 55 mg of Example 37: TLC (EtOAc/MeOH(7:3): R_(f)=0.25; ¹H NMR (DMSO-d₆, 400 MHz) δ11.42 (d, 1H, J=8.93),7.95 (m. 2H), 7.70 (dd, 1H, J=1.78, 7.69), 7.51 (m, 4H), 7.23 (m, 4H),6.88 (d, 2H, J=8.50), 5.36 (s, 1H), 4.22 (m, 2H), 4.16 (brs, 1H), 3.18(m, 1H), 2.94 (m, 2H), 2.84 (m, 1H), 2.40 (s, 3H), 1.70 (s, 3H); lowresolution MS (ES−)m/e 545.1 (M-H); RP-HPLC (Vydac C-18, 25 cm×4.6 mm;30-100% CH₃CN in H₂O) with 0.1% HCO₂H buffer: 30 minutes; 1 mL/min:t_(r)=19.47 min (t_(o)=1.43).

Example 38(2S)-2-{[(Z)-3-(2,3-difluorophenyl)-1-methyl-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

The title compound was prepared (as described above for the preparationof Example 12) from 120 mg (0.33 mmol) of Intermediate 45 and 59 mg(0.33 mmol) of Intermediate 40 to yield 32 mg (18% yield) of Example 38:TLC (DCM/MeOH (4:1): R_(f)=0.72; ¹H NMR (DMSO-d₆, 300 MHz) δ11.43 (d,1H, J=9.8), 7.97 (m, 2H), 7.56 (m, 5 h), 7.28 (m, 1H), 7.19 (d, 2H,J=8.0) 6.91 (d, 2H, J=8.0), 5.34 (s, 1H), 4.21 (m, 3H), 3.21 (m, 2H),2.98 (t, 2H, J=6.6), 2.84 9 m, 1H), 2.40 (s, 3H), 1.78 (s, 3H); lowresolution MS (ES+)m/e 547 (MH⁺).

Example 39(2S)-2-{[(Z)-3-(2-hydroxyphenyl)-1-methyl-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

A solution of 100 mg (0.27 mmol) of Intermediate 45 and 58 mg (0.33mmol) of 2-(acetoacetyl)phenol (Aldrich Chemical Co.) in 5.0 mL MeOH ,1.0 mL trimethyl orthoformate, and 4A sieves (50 mg) was refluxed at 80°C. for 16 h. The reaction solution was concentrated and purified bysilica gel flash column chromatography using DCM/MeOH 20/1 to 10/1 aseluent to afford 135 mg of Example 39: TLC (DCM/MeOH (10:1): R_(f)=0.32;¹H NMR (DMSO-d₆) δ11.16 (d, 1H, J=8.72), 7.96 (m, 2H), 7.78 (m, 1H),7.54 (m, 3H), 7.33 (m, 1H), 7.20 (m, 2H), 6.84 (m, 4H), 5.69 (s, 1H),4.26 (m, 2H), 4.17 (br s, 1H), 3.20 (dd, 1H, J=3.93, 13.67), 2.95 (m,2H), 2.81 (m, 1H), 2.40 (s, 3H), 1.75 (s, 3H); low resolution MS (ES+)m/e 527.0 (MH⁺); RP-HPLC (Vydac C-18, 25 cm×4.6 mm; 50-100% CH₃CN inH₂O) with 0.1% HCO₂H buffer: 30 minutes; 1 mL/min: t_(f)=15.97 min(t_(o)=1.43).

Example 40(2S)-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}-2-{[(Z)-3-oxo-3-phenyl]-1-propyl-1-propenyl]amino}propanoicacid

The title compound was prepared as described above for the preparationof Example 2, from 1.0 g (2.05 mmol) of Intermediate 45 (as the TFAsalt) and 0.8 g (4.2 mmol) of Intermediate 17 to yield 400 mg of Example40 as a white solid: ¹H NMR (DMSO-d₆, 400 MHz) δ11.55 (d, 1H, J=9.6),7.87 (m, 2H), 7.75 (m, 2H), 7.45 (m, 3H), 7.35 (m, 3H), 7.10 (d, 2H,J=8.6), 6.80 (d, 2H, J=8.5), 5.52 (s, 1H), 4.12 (t, 2H, J=6.6), 4.07 (m,1H), 3.21 (dd, 1H, J=13.7, 3.7), 2.85 (t, 2H, J=6.5), 2.73(dd, 1H,J=13.7, 8.6), 2.3 (s, 3H) 1.90 (m, 2H), 1.4-1.25 (m, 2H), 0.76 (t, 3H,J=7.4); low resolution MS (ES+)m/e 539.2 (MH⁺).

Example 41(2S)-2-{[(Z)-3-(4-methoxyphenyl)-1-methyl-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

The title compound was prepared (as described above for the preparationof Example 2) from 100 mg (0.27 mmol) of Intermediate 45 and 52 mg (0.27mmol) of Intermediate 22 to yield 126 mg of Example 41. TLC (EtOAc/MeOH(7:3): R_(f)=0.44: ¹H NMR (DMSO-d₆, 400 MHz) δ11.30 (d, 1H, J=7.00),7.87 (m. 2H), 7.73 (d, 2H, J=8.72), 7.45 (m, 3H), 7.10 (d, 2H, J=8.37),6.88 (d, 2H, J=8.89), 6.77 (d, 2H, J=8.37), 5.74 (s, 1H), 4.11 (m, 2H),4.01(m, br, 1H), 3.13 (m, 1H), 2.86 (m, 2H), 2.72 (m, 1H), 2.31 (s, 3H),1.65 (s, 3H); low resolution MS (ES−) m/e 539 (M-H); RP-HPLC (VydacC-18, 25 cm×4.6 mm; 10-50% CH₃CN in H₂O) with 0.1% HCO₂H buffer: 30minutes

Example 42(2S)-3-(4-{2-[2-(4-methoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)-2-{[(Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]amino}propanoicacid

The title compound was prepared (as described above for the preparationof Example 2) from 75 mg (0.19 mmol) of Intermediate 49 and 31 mg (0.19mmol) of benzoylacetone to yield 30 mg of Example 42: TLC (DCM/MeOH(4:1): R_(f)=0.45; ¹H NMR (DMSO-d₆, 400 MHz) δ11.5 (d, 1H, J=9.1), 7.89(d, 2H, J=8.8), 7.84 (m, 2H), 7.45 (m, 3H), 7.18 (d, 2H, J=8.4); 7.09(d, 2H, J=8.8), 6.88 (d, 2H, J=8.6), 5.63 (s, 1H), 4.2 (t, 2H, J=6.5),4.1 (m, 1H), 3.86 (s, 3H), 3.2 (m, 1H), 2.93 (t, 2H, J=6.6), 2.83 (dd,1H, J=13.2, 6.4), 2.37 (s, 3H), 1.76 (s, 3H); low resolution MS (ES−)m/e539.2 (MH−).

Example 43(2S)-2-{[(Z)-3-cyclohexyl-1-methyl-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

The title compound was prepared (as described above for the preparationof Example 2) from 428 mg (0.89 mmol) of Intermediate 45 (as the TFAsalt) and 150 mg (0.89 mmol) of Intermediate 33 to yield 245 mg (53%yield) of Example 43 as a solid beige-colored glass: TLC (DCM/MeOH(4:1): R_(f)=0.69; ¹H NMR (DMSO-d₆, 400 MHz) δ10.79 (d, 1H, J=9.0), 7.89(m, 2H), 7.50-7.41 (m, 3H), 7.05 (d, 2H, J=8.4), 6.77 (d, 2H, J=8.4),4.7 (s, 1H), 4.12 (t, 2H, J=6.5), 3.9 (br s, 1H), ), 3.04 (dd, 1H,J=13.6, 4.0), 2.87 (t, 2H, J=6.5), 2.64 (dd, 1H, J=13.6, 8.9), 2.32 (s,3H), 1.9 (m, 1H), 1.6 (m, 4H), 1.5 (s, 3H), 1.25-1.05 (m, 4H): lowresolution MS (ES+)m/e 517.3 (MH⁺).

Example 44(2S)-3-(4-{2-[2-(4-isopropoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)-2-{[(Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]amino}propanoicacid

The title compound was prepared (as described above for the preparationof Example 2) from 75 mg (0.18 mmol) of Intermediate 51 and 32 mg (0.194mmol) of benzoylacetone to yield 55 mg of Example 44: TLC (DCM/MeOH(4:1): R_(f)=0.50; ¹H NMR (DMSO-d₆, 400 MHz) δ11.5 (d, 1H, J=9.0), 7.85(m, 4H), 7.45 (m, 3H), 7.18 (d, 2H, J=8.4); 7.06 (d, 2H, J=8.8), 6.87(d, 2H, J=8.5), 5.82 (s, 1H), 4.74 (m, 1H), 4.19 (t, 2H, J=6.6), 4.1 (m,1H), 3.19 (m, 1H), 2.92 (t, 2H, J=6.6), 2.81 (dd, 1H, J=13.9. 9.1), 2.36(s, 3H), 1.74 (s, 3H), 1.34 (d, 6H, J=6.0); low resolution MS (ES−)m/e567.2 (M-)

Example 45(2S)-2-{[(Z)-1-heptyl-3-oxo-3-phenyl-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

The title compound was prepared as described above for the preparationof Example 2, from 102 mg (0.28 mmol) of Intermediate 45 and 69 mg (0.28mmol) of Intermediate 19 to yield 77 mg of Example 45: TLC (EtOAc/MeOH ,713): R_(f)=0.56; ¹H NMR (DMSO-d₆, 400 MHz) δ11.55 (d, 1H, J=9.6), 7.86(d, 2H, J=6.8), 7.76 (d, 2H, J=6.4), 7.46. (m, 3H), 7.38 (m, 3H), 7.10(d, 2H, J=8.4), 6.78 (d, 2H, J=8.4), 5.5 (s, 1H), 4.10 (t, 2H, J=6.6),4.0 (m, 1H), 3.16 (m, 1H), 2.86 (t, 2H, J=6.5), 2.69 (dd, 1H, J=13.6,9.6), 2.31 (s, 3H), 1.87 (m, 2H), 1.25-1.1 (m, 10H), 0.78 (t, 3H,J=6.8); low resolution MS (ES+)m/e 595.1 (MH⁺).

Example 46(2S)-2-{[(Z)-1-methyl-3-(3-methylphenyl)-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

The title compound was prepared (as described above for the preparationof Example 2) from 100 mg (0.27 mmol) of Intermediate 45 and 48 mg (0.27mmol) of Intermediate 21 to yield 104 mg of Example 46. ¹H NMR (DMSO-d₆,400 MHz) δ11.47 (d, 1H, J=9.06), 7.95 (m. 2H), 7.65 (m, 2H), 7.54 (m,3H), 7.31 (m, 2H), 7.19 (d, 2H, J=8.51), 6.88 (d, 2H, J=8.51), 5.64 (s,1H), 4.23 (m, 1H), 4.23 (m, 3H), 3.21 (m, 1H), 2.96 (m, 2H), 2.86 (m,1H), 2.60 (s, 3H), 1.80 (s, 3H); low resolution MS (ES) m/e 525.2 (MH⁺);RP-HPLC (Vydac C-18, 25 cm×4.6 mm; 50-100% CH₃CN in H₂O) with 0.1% HCO₂Hbuffer 30 minutes; 1 mL/min: t_(f)15.57 min (t_(o)=1.43).

Example 47(2S)-2-{[(Z)-1-ethyl-3-oxo-3-phenyl-1-propenyl]amino}-3-(4-{2-[2-(4-methoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)propanoicacid

The title compound was prepared (as described above for the preparationof Example 2) from 100 mg (0.25 mmol) of Intermediate 49 and 45 mg (0.25mmol) of Intermediate 16 to yield 95 mg (68% yield) of Example 47 as asolid: TLC R_(f)=0.2-0.3 (slight streak, 4/1, CH₂Cl₂/MeOH); ¹H NMR(DMSO-d₆, 400 MHz) δ11.5 (d, 1H, J=9.0), 7.85 (m, 4H), 7.45 (m, 3H),7.18 (d, 2H, J=8.4); 7.06 (d, 2H, J=8.8), 6.87 (d, 2H, J=8.5), 5.82 (s,1H), 4.74 (m, 1H), 4.19 (t, 2H, J=6.6), 4.1 (m, 1H), 3.19 (m, 1H), 2.92(t, 2H, J=6.6), 2.81 (dd, 1H, J=13.9, 9.1), 2.36 (s, 3H), 1.74 (s, 3H),1; low resolution MS (ES+)m/e 555.1 (MH⁺);

Example 48(2S)-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}-2{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoicacid

The title compound was prepared (as described above for the preparationof Example 12) from 1.3 g (3.55 mmol) of Intermediate 45 and 0.7 g (3.55mmol) of Intermediate 44 to yield 0.84 g (42% yield) of Example 48 as asolid: TLC (DCM/MeOH (4:1): R_(f)=0.55; ¹H NMR (DMSO-d₆, 300 MHz) δ10.99(s, 1H), 7.94 (m, 4H), 7.68 (m, 6H), 7.14 (d, 2H, J=8.4), 6.84 (d, 2H,J=8.4), 6.21 (s, 1H), 4.19 (m, 3H), 3.17 (m, 1H), 2.92-2.85 (m, 3H),2.36 (s, 3H); low resolution MS (ES+)m/e 565.0 (MH⁺).

Example 49(2S)-3-{4-[2-(5-methyl-2-phenyl-1,3-thiazol-4-yl)ethoxy]phenyl}-2{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoicacid

The title compound was prepared (as described above for the preparationof Example 12) from 120 mg (0.31 mmol) of Intermediate 46 and 62 mg(0.31 mmol) of Intermediate 44 to yield 78 mg of Example 49: TLC(DCM/MeOH (4:1): R_(f)=0.58; ¹H NMR (DMSO-d₆, 300 MHz) δ10.92 (br s,1H), 7.88 (d, 2H, J=), 7.81 (m, 2H), 7.56-7.37 (m, 6H), 7.01 (d, 2H,J=8.5), 6.78 (d, 2H, J=8.3), 6.13 (s, 1H), 4.19 (t, 2H, J=6.5), 4.10 (brs, 1H), 3.15-3.11 (m, 1H), 3.05 (t, 2H, J=6.6), 2.87 (dd, 1H, J=13.7,7.7), 2.37 (s, 3H); low resolution MS (ES+)m/e 581.0 (MH⁺).

Example 50(2S)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-(4-{2-[2-(4-fluorophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)propanoicacid

The title compound was prepared (as described above for the preparationof Example 2) from 150 mg (0.39 mmol) of Intermediate 46 and 95 mg (0.39mmol) of Intermediate 25 to yield 79 mg (33% yield) of Example 50: TLC(DCM/MeOH, 4/1): R_(f)=0.62; ¹H NMR (DMSO-d₆, 300 MHz) δ11.59 (d, 1H,J=9.0), 7.97-7.88 (m, 4H), 7.72 (d, 2H, J=8.4), 7.29 (t, 2H, J=9.0),7.11 (d, 2H, J=8.4), 6.78 (d, 2H, J=8.4), 5.59 (s, 1H), 4.11 (m, 3H),3.17 (m, 2H), 2.85 (t, 2H, J=6.3), 2.77 (m, 1H), 2.29 (s, 3H), 2.03 (m,2H), 0.91 (t, 3H, J=7.5); low resolution MS (ES⁺)m/e 611.2 (MH⁺).

Example 51(2S)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-(4-{2-[2(4-isopropoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)propanoicacid

The title compound was prepared (as described above for the preparationof Example 2) from 151 mg (0.39 mmol) of Intermediate 51 and 92 mg (0.39mmol) of Intermediate 25 to yield 91 mg (36% yield) of Example 51: TLC(DCM/MeOH, 4/1): R_(f)=0.60; ¹H NMR (DMSO-d₆, 300 MHz) δ11.6 (d, 1H,J=9.6), 7.96 (d, 2H, J=8.1), 7.81-7.70 (m, 4H), 7.10 (d, 2H, J=8.4),6.96 (d, 2H, J=8.7), 6.78 (d, 2H, J=8.4), 5.59 (s, 1H), 4.62 (sept, 1H,J=6.0), 4.13 (m, 3H), 3.16 (m, 1H), 2.84-2.72 (m, 3H), 2.26 (s, 3H),2.05-1.96 (m, 2H), 1.24 (d, 6H, J=6.0), 0.91 (t, 3H, J=7.5); lowresolution MS (ES⁺)m/e 651.3 (MH⁺).

Example 52(2S)-2-({(Z)-1-ethyl-3oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)3-(4-{2-[2-(4-methoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)propanoicacid

The title compound was prepared (as described above for the preparationof Example 2) from 150 mg (0.38 mmol) of Intermediate 49 and 93 mg (0.38mmol) of Intermediate 25 to yield 45 mg (19% yield) of Example 52: TLC(DCM/MeOH, 4/1): R_(f)=0.63; ¹H NMR (DMSO-d₆, 300 MHz) δ11.6 (d, 1H,J=9.6), 7.96 (d, 2H, J=8.1), 7.81-7.70 (m, 4H), 7.11 (d, 2H, J=8.4), 7.0(d, 2H, J=8.7), 6.78 (d, 2H, J=8.4), 5.6 (s, 1H), 4.18-4.07 (m, 3H),3.77 (s, 3H), 3.17 (m, 1H), 2.85-2.72 (m, 3H), 2.26 (s, 3H), 2.05-1.96(m, 2H), 0.91 (t, 3H, J=7.5); low resolution MS (ES⁺)m/e 623.2 (MH⁺).

Example 53(2S)-3-(4-{2-[2-(4-fluorophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoicacid

The title compound was prepared (as described above for the preparationof Example 12) from 203 mg (0.53 mmol) of Intermediate 46 and 130 mg(0.63 mmol) of Intermediate 44 to yield 154 mg (50% yield) of Example53: TLC (DCM/MeOH, 4/1): R_(f)=0.65; ¹H NMR (DMSO-d₆, 400 MHz) δ11.5 (d,1H, J=8.9), 7.95 (d, 2H, J=7.2), 7.77 (d, 2H, J=8.7), 7.72 (d, 2H,J=8.2), 7.1 (d, 2H, J=8.4), 6.97 (d, 2H, J=8.9), 6.79 (d, 2H, J=8.5),5.58 (s, 1H), 4.65 (m, 1H), 4.11 (t, 2H, J=6.5), 4.1 (m, 1H), 3.16 (dd,1H, J=13.7, 3.6), 2.84 (t, 2H, J=6.5), 2.74 (dd,1H, 13.7, 9.0), 2.28 (s,3H), 1.67 (s, 3H), 1.25 (d, 6H, J=6.0); low resolution MS (ES⁺)m/e 637.1(MH⁺)

Example 54(2S)-2-{[(Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]amino}-3-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenyl}propanoicacid

The title compound was prepared (as described above for the preparationof example 1) from a suspension of 113 mg (0.32 mmol) of Intermediate 54and 52 mg (0.32 mmol) of benzoylacetone to yield 44 mg (28%) of example54: TLC (DCM/MeOH, 4/1): R_(f)=0.55; ¹H NMR (DMSO-d₆, 300 MHz) δ11.43(d, 1H, J=9.0), 7.92-7.88 (m, 2H), 7.8 (m, 2H), 7.48 (m, 3H), 7.38-7.38(m, 3H), 7.16 (d, 2H, J=8.4), 6.9 (d, 2H, J=8.4), 5.53 (s, 1H), 4.91 (s,1H), 4.15 (m, 1H), 3.2 (m, 2H), 2.83-2.74 (m, 1H), 2.37 (s, 3H), 1.67(s, 3H); low resolution MS (ES⁺)m/e 497.07 (MH⁺).

Example 55(2S)-3-{4-[2-(5-ethyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}-2-{[(Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]amino}propanoicacid

The title compound was prepared (as described above for the preparationof example 1) from a suspension of 205 mg (0.54 mmol) of Intermediate 52and 87 mg (0.54 mmol) of benzoylacetone to yield 145 mg (51%) of example55: TLC (DCM/MeOH, 4/1): R_(f)=0.60; ¹H NMR (DMSO-d₆, 300 MHz) δ11.42(d, 1H, J=9.0), 7.89-7.86 (m, 2H), 7.77-7.74 (m, 2H), 7.48-7.32 (m, 6H),7.11 (d, 2H, J=8.4), 6.77 (d, 2H, J=8.4), 5.53 (s, 1H), 4.1 (t, 1H,J=6.3), 3.2-3.14 (m, 2H), 2.86 (t, 2H, J=6.3), 2.79-2.74 (m, 1H), 2.67(q, 2H, J=7.5), 1.65 (s, 3H), 1.17 (t, 3H, J=7.5); low resolution MS(ES⁺)m/e 525.2 (MH⁺).

Example 56(2S)-2-{[(Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]amino}-3-{4-[2-(2-phenyl-5-propyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid

The title compound was prepared (as described above for the preparationof example 1) from a suspension of 204 mg (0.52 mmol) of Intermediate 53and 84 mg (0.52 mmol) of benzoylacetone to yield 137 mg (49%) of example56: TLC (DCM/MeOH, 4/1): R_(f)=0.60; ¹H NMR (DMSO-d₆, 300 MHz) δ11.42(d, 1H, J=9.0), 7.89-7.86 (m, 2H), 7.77-7.74 (m, 2H), 7.49-7.32 (m, 6H),7.11 (d, 2H, J=8.4), 6.77 (d, 2H, J=8.4), 5.53 (s, 1H), 4.1 (t, 1H,J=6.3), 3.19-3.13 (m, 2H), 2.86 (t, 2H, J=6.3), 2.78-2.71 (m, 1H), 2.64(t, 1H, J=7.2), 1.65-1.54 (m, 5H), 0.88 (t, 3H, J=7.5); low resolutionMS (ES⁺)m/e 539.19 (MH⁺).

Example 57(2S)-2-{[(Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]amino}-3-{4-[3-(5-methyl-2-phenyl-1,3-oxazol-4-yl)propoxy]phenyl}propanoicacid

The title compound was prepared (as described above for the preparationof example 1) from a suspension of 205 mg (0.54 mmol) of Intermediate 55and 88 mg (0.54 mmol) of benzoylacetone to yield 142 mg (50% yield) ofexample 57: TLC (DCM/MeOH, 4/1): R_(f)=0.66; ¹H NMR (DMSO-d₆, 300 MHz)δ11.44 (d, 1H, J=9.0), 7.88-7.85 (m, 2H), 7.78-7.75 (m, 2H), 7.49-7.43(m, 3H), 7.37-7.32 (m, 3H), 7.12 (d, 2H, J=8.4), 6.78 (d, 2H, J=8.4),5.54 (s, 1H), 4.13 (m, 1H), 3.87 (t, 1H, J=6.0), 3.22-3.16 (m, 1H), 2.77(d, 1H, J=14.4, 9.2), 2.56 (t, 2H, J=7.2), 2.22 (s, 3H), 2.00-1.93 (m,2H), 1.66 (s, 3H); low resolution MS (ES⁺)m/e 525.15 (MH⁺).

Example 58(2S)-3-{4-[2-(5-ethyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoicacid

A mixture of 100 mg (0. 26 mmol, 1.0 equivalent) of Intermediate 52, 110mg (0.39 mmol, 1.5 equivalents) of Intermediate 44, and 0.14 mL (0.8mmol, 3.0 equivalents) of DIEA in 2 mL of MeOH was stirred for 2.5 hoursat ambient temperature (22° C.). The solvent was evaporated underreduced pressure. The residue was taken into EtOAc (20 mL) and washedwith 10 mL 0.1 N HCl solution and 10 mL brine. The organics were driedover Na₂SO₄, filtered, concentrated, and the residue purified directlyby silica gel chromatography. Elution with 10%-20% MeOH in EtOAc gave 55mg (36% yield) of the title compound as a solid after drying undervacuum for several hours: TLC (DCM/MeOH, 4/1): R_(f)=0.65; ¹H NMR(DMSO-d₆, 400 MHz) δ10.95 (br s, 1H), 7.88-7.93 (m, 4H), 7.52-7.41 (m,6H), 7.72 (d, 2H, J=8.2), 7.02 (d, 2H, J=8.4), 6.73 (d, 2H, J=8.5), 6.06(s, 1H), 4.09 (t, 2H, J=6.5), 3.99 (m, 1H), 3.0 (m, 1H, NH), 2.86-2.79(m, 4H), 2.66 (q, 2H, 7.5), 1.15 (t, 3H, J=7.5); low resolution MS(ES+)m/e 579.08 (MH⁺)

Example 59(2S)-3-{4-[3-(5-methyl-2-phenyl-1,3-oxazol-4-yl)propoxy]phenyl}-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoicacid

The title compound was prepared (as described above for the preparationof Example 58) from 100 mg (0.26 mmol) of Intermediate 55 and 110 mg(0.39 mmol) of Intermediate 44 to yield 65 mg (42% yield) of Example 59:TLC (DCM/MeOH, 4/1): R_(f)=0.58; ¹H NMR (DMSO-d₆, 400 MHz) δ10.74 (d,1H, J=9.4), 7.90 (d, 2H, J=7.5), 7.86-7.82 (m, 2H), 7.54 (m, 1H),7.48-7.40 (m, 5H), 7.09 (d, 2H, J=8.4), 6.81 (d, 2H, J=8.4), 6.25 (s,1H), 4.3 (br s, 1H), 3.89 (t, 2H, J=6.1), 3.09 (dd, 1H, J=14.0, 4.8),2.96 (dd, 1H, 14.0, 7.9). 2.2 (s, 3H), 2.0-1.92 (m, 2H); low resolutionMS (ES+)m/e 579.08 (MH⁺)

Example 60(2S)-3-{4-[2-(5-ethyl-2-phenyl-1,3-thiazol-4-yl)ethoxy]phenyl}-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoicacid

The title compound was prepared (as described above for the preparationof Example 58) from 180 mg (0.35 mmol) of Intermediate 57 (as its TFAsalt) and 148 mg (0.53 mmol) of Intermediate 44 to yield 113 mg (54%yield) of Example 60: TLC (DCM/MeOH, 85/15): R_(f)=0.50; ¹H NMR (DMSO-d₆, 300 MHz) δ10.72 (d, 1H, J=10.3), 7.94 (d, 2H, J=7.3), 7.87-7.83 (m,2H), 7.67-7.39 (m, 5H), 7.13 (d, 2H, J=8.6), 6.86 (d, 2H, J=8.5), 6.32(s, 1H, 4.26 (t, 2H, J=6.5), 3.17-3.01 (m, 4H), 2.81 (q, 2H, J=7.4),1.22 (t, 3H, J=7.4); low resolution MS (ES+)m/e 594.9 (MH⁺)

Example 61(2S)-3-(4-{2-[5-ethyl-2-(4-fluorophenyl)-1,3-oxazol-4-yl]ethoxy}phenyl)-2-{[(Z)-3-oxo-3-phenyl-1-trifluoromethyl)-1-propenyl]amino}propanoicacid

The title compound was prepared (as described above for the preparationof Example 58) from 130 mg (0.26 mmol) of Intermediate 58, 106 mg (0.38mmol) of Intermediate 44, and 0.14 mL diisopropylethylamine in 5 mLMeOH. The crude product was recrystallized from hot CH₃CN to yield 67 mg(43% yield) of Example 61: TLC (DCM/MeOH, 85/15): R_(f)=0.44; ¹H NMR(DMSO-d₆, 300 MHz) δ10.72 (d, 1H, J=10.3), 7.97-7.92 (m, 4H), 7.62-7.56(m, 1H), 7.52-7.46 (m, 3H), 7.32 (t, 2H, J=8.7), 7.13 (d, 2H, J=8.6),6.85 (d, 2H, J=8.6), 6.32 (s, 1H), 4.35 (m, 1H), 4.16 (t, 2H, J=6.5),3.13 (dd, 1H, J=14.0, 4.8), 3.02 (dd, 1H, J=14.0, 7.7), 2.89 (t, 2H,J=6.5), 2.69 (q, 2H, J=7.4), 1.19 (t, 3H, J=7.5); low resolution MS(ES+)m/e 596.9 (MH⁺).

Example 62(2S)-3-(4-{3-[5-ethyl-2-(4-fluorophenyl)-1,3-oxazol-4-yl]propoxy}phenyl)-2{[(Z)-3-oxo-3-phenyl-1-trifluoromethyl)-1-propenyl]amino}propanoicacid

The title compound was prepared (as described above for the preparationof Example 58) from 200 mg (0.38 mmol) of Intermediate 59, 127 mg (0.57mmol) of Intermediate 44, and 0.2 mL diisopropylethylamine in 2.5 mLMeOH. The crude product was recrystallized from hot CH₃CN to yield 106mg (46% yield) of Example 62: TLC (DCM/MeOH, 4/1): R_(f)=0.61; ¹H NMR(DMSO-d₆, 300 MHz) δ10.72 (d, 1H, J=10.2), 7.95-7.91 (m, 4H), 7.76-7.61(m, 3H), 7.31 (t, 2H, J=8.7), 7.13 (d, 2H, J=8.1), 6.85 (d, 2H, J=8.4),6.32 (s, 1H), 4.42-4.37 (m, 1H), 3.92 (t, 1H, J=5.7), 3.15-2.98 (m, 3H),2.60-2.65 (m 4H), 2.0 (t, 2H, J=6.3), 1.10 (t, 3H, J=7.5); lowresolution MS (ES⁺)m/e 610.96 (MH⁺).

Example 63(2S)-3-(4-{2-[ethyl-2-4-fluorophenyl)-1,3-thiazol-4-yl]ethoxy}phenyl)-2{[(E)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoicacid

The title compound was prepared (as described above for the preparationof Example 58) from 130 mg (0.25 mmol) of Intermediate 56, 103 mg (0.37mmol) of Intermediate 44, and 0.17 mL diisopropylethylamine in 5 mLMeOH. The crude product was recrystallized from hot CH₃CN to yield 110mg (72% yield) of Example 63: TLC (DCM/MeOH, 85/15): R_(f)=0.45; ¹H NMR(DMSO-d₆, 300 MHz) δ10.72 (d, 1H, J=10.2), 7.96-7.86 (m, 4H), 7.59 (m,1H), 7.52-7.46 (m, 3H), 7.28 (t, 2H, J=8.8), 7.13 (d, 2H, J=8.6), 6.85(d, 2H, J=8.5), 6.32 (s, 1H), 4.38 (m, 1H), 4.25 (t, 2H, J=6.5),3.31-2.98 (m, 4H), 2.81 (q, 2H, J=7.4), 1.22 (t, 3H, J=7.4); lowresolution MS (ES⁺)m/e 612.9 (MH⁺)

Example 64(2S)-3-(4-{3-[5-ethyl-2-(4-fluorophenyl)-1,3-oxazol-4-yl]propoxy}phenyl)-2-({(Z)-1-ethyl3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoic acid

The title compound was prepared (as described above for the preparationof Example 2) from 95 mg (0.18 mmol) of Intermediate 59 (TFA Salt), 44mg (0.18 mmol) of Intermediate 25, and 0.055 mL triethylamine in MeOH(1.5 mL) and trimethylorthoformate (0.5 mL) to yield 44 mg (38% yield)of Example 64 after silica gel chromatography (5%-15% MeOH in DCMelution): TLC (DCM/MeOH, 4/1): R_(f)=0.53; ¹H NMR (DMSO-d₆, 300 MHz)δ11.63 (d, 1H, J=9.3), 7.99-7.89 (m, 4H), 7.73 (d, 2H, J=8.1), 7.30 (t,2H, J=8.7), 7.13 (d, 2H, J=8.1), 6.79 (d, 2H, J=8.1), 5.62 (s, 1H), 4.20(m, 1H), 3.87 (m, 2H), 3.20 (m, 2H), 2.77 (m, 2H), 2.61-2.54 (m, 4H),2.05-1.96 (m, 4H), 1.10 (t, 3H, J=7.2), 0.92 (t, 3H, J=7.5); lowresolution MS (ES⁺)m/e 638.93 (MH⁺).

Example 65(2S)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-{4-[3-(5-ethyl-2-phenyl-1,3-oxazol-4-yl)propoxy]phenyl}propanoicacid

The title compound was prepared (as described above for the preparationof Example 2) from 50 mg (0.13 mmol) of Intermediate 60, 31 mg (0.13mmol) of Intermediate 25, and 0.044 mL triethylamine in MeOH (1.0 mL)and trimethylorthoformate (0.5 mL) to yield 22 mg (28% yield) of Example65 after silica gel chromatography (5%-15% MeOH in DCM elution): TLC(DCM/MeOH, 4/1): R_(f)=0.50; ¹H NMR (DMSO-d₆, 300 MHz) δ11.70 (d, 1H,J=9.6), 8.05 (d, 2H, J=7.8), 7.95 (d, 2H, J=7.8), 7.81 (d, 2H, J=8.1),7.55-7.52 (m, 3H), 7.20 (d, 2H, J=8.4), 6.86 (d, 2H, J=8.4), 5.69 (s,1H), 4.28-4.2 1H), 3.96 (d, 2H, J=6.0), 3.28-3.20 (m, 2H), 2.89-2.81 (m,1H), 2.72-2.63 (m, 4H), 2.05-1.96 (m, 4H), 1.18 (t, 3H, J=7.5), 0.99 (t,3H, J=7.5); low resolution MS (ES⁺)m/e 620.98 (MH⁺).

Example 66(2S)-3-(4-{3-[5-ethyl-2-(4-fluorophenyl)-1,3-oxazol-4-yl]propoxy}phenyl)-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoicacid

The title compound was prepared (as described above for the preparationof Example 2) from 90 mg (0.17 mmol) of Intermediate 59, 40 mg (0.17mmol) of Intermediate 24, and 0.05 mL triethylamine in MeOH (1.5 mL) andtrimethylorthoformate (0.5 mL) to yield 54 mg (51% yield) of Example 66after silica gel chromatography (5%-15% MeOH in DCM): TLC (DCM/MeOH,4/1): R_(f)=0.60; ¹H NMR (DMSO-d₆, 300 MHz) δ11.53 (d, 1H, J=9.0),7.98-7.90 (m, 4H), 7.73 (d, 2H, J=8.4), 7.30 (t, 2H, J=8.7), 7.13 (d,2H, J=8.4), 6.79 (d, 2H, J=8.4), 5.61 (s, 1H), 4.23-4.19 (m, 1H), 3.89(t, 2H, J=6.0), 3.22-3.17 (m, 2H), 2.83-2.75 (m, 2H), 2.64-2.55 (m, 4H),1.97 (t, 2H, J=6.3), 1.71 (s, 3H), 1.10 (t, 3H, J=7.5); low resolutionMS (ES⁺)m/e 625.15 (MH⁺).

Example 67(2S)-3-{4-[3-(5-ethyl-2-phenyl-1,3-oxazol-4-yl)propoxy]phenyl}-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoicacid

The title compound was prepared (as described above for the preparationof Example 2) from 57 mg (0.14 mmol) of Intermediate 60, 33 mg (0.14mmol) of Intermediate 24, and 0.042 mL triethylamine in MeOH (1.5 mL)and trimethylorthoformate (0.5 mL) to yield 24 mg (28% yield) of Example67 after silica gel chromatography (5%-15% MeOH in DCM): TLC (DCM/MeOH,4/1): R_(f)=0.62; ¹H NMR (DMSO-d₆, 300 MHz) δ11.53 (d,1H, J=9.0), 7.97(d, 2H, J=8.4), 7.89 (d, 2H, J=7.8), 7.73 (d, 2H, J=8.4), 7.46 (m, 3H),7.97 (d, 2H, J=8.1), 6.79 (d, 2H, J=8.4), 5.62 (s, 1H), 4.25-4.19 (m,1H), 3.90 (t, 2H, J=6.0), 3.21-3.15 (m, 1H), 2.58-2.83 (m, 5H), 1.98 (t,2H, J=5.7), 1.72 (s, 3H), 1.11 (t, 3H, J=7.5); low resolution MS(ES⁺)m/e 607.18 (MH⁺).

Example 68(2S)-3-{4-[3-(5-ethyl-2-phenyl-1,3-oxazol-4-yl)propoxy]phenyl}-2-{[(Z)-3-oxo-3-phenyl-1(trifluoromethyl)-1-propenyl]amino}propanoic acid

The title compound was prepared (as described above for the preparationof Example 58) from 100 mg (0.25 mmol) of Intermediate 60, 85 mg (0.38mmol) of Intermediate 44, and 0.14 mL diisopropylethylamine in 2.0 mLMeOH. Attempted recrystallization from hot CH₃CN without success. Silicagel chromatography with MeOH/DCM (10%-20%) gave 68 mg (45% yield) ofExample 68: TLC (DCM/MeOH, 4/1): R_(f)=0.60; ¹H NMR (DMSO-d₆, 300 MHz)δ10.96 (br s, 1H), 7.90-7.87 (m, 4H), 7.54-7.46 (m, 6H), 7.07 (d, 2H,J=8.4), 6.78 (d, 2H, J=8.1), 6.12 (s, 1H), 4.11-4.03 (m, 1H), 3.89 (t,2H, J=6.0), 3.12-3.07 (m, 1H), 2.91-2.83 (m, 1H), 2.66-2.57 (m, 4H),1.98 (t, 2H, J=5.7), 1.11 (t, 3H, J=7.5); low resolution MS (ES⁺)m/e593.02 (MH⁺).

Example 69(2S)-3-{4-[(5-ethyl-2-phenyl-1,3-thiazol-4-yl)methoxy]phenyl}-2-{[(Z)-3-oxo-3-phenyl-1-trifluoromethyl)-1-propenyl]amino}propanoicacid

The title compound was prepared (as described above for the preparationof Example 58) from 1.5 g (3.02 mmol) of Intermediate 62, 1.01 g (4.53mmol) of Intermediate 44, and 1.6 mL diisopropylethylamine in 20 mLMeOH. Attempted recrystallization from hot CH₃CN without success. Silicagel chromatography with MeOH/DCM (10%-20%) gave 1.05 g (60% yield) ofExample 69: TLC (DCM/MeOH, 4/1): R_(f)=0.43; ¹H NMR (DMSO-d₆, 300 MHz)δ10.98 (br s, 1H), 7.91-7.85 (m, 4H), 7.55-7.45 (m, 6H), 7.11 (d, 2H,J=8.4), 6.92 (d, 2H, J=8.4), 6.15 (s, 1H), 5.07 (s, 2H), 4.13-4.06 (m,1H), 3.16-3.09 (m, 1H), 2.95-2.85 (m, 4H), 1.21 (t, 3H, J=7.5); lowresolution MS (ES⁺)m/e 580.95 (MH⁺).

Example 70 (2S)-3-{4-[(5-ethyl-2-phenyl-1,3-thiazol-4-yl)methoxy]phenyl}-2-({(Z)-1-methyl-3-oxo-3-[4-(trIfluoromethyl)phenyl]-1-propenyl}amino)propanoicacid

The title compound was prepared (as described above for the preparationof Example 2) from 1.35 g (2.72 mmol) of Intermediate 62, 630 mg (2.72mmol) of Intermediate 24, and 0.8 mL triethylamine in MeOH (20 mL) andtrimethylorthoformate (5 mL) to yield 1.04 g (65% yield) of Example 70after silica gel chromatography (5%-15% MeOH in DCM): TLC (DCM/MeOH,4/1): R_(f)=0.45; ¹H NMR (DMSO-d₆, 300 MHz) δ11.57 (d, 1H, J=8.7), 7.96(d, 2H, J=8.4), 7.85 (m, 2H), 7.71 (d, 2H, J=8.4), 7.44 (m, 3H), 6.92(d, 2H, J=8.4), 5.6 (s, 1H), 5.05 (s, 2H), 4.21-4.27 (m, 1H), 3.27-3.22(m, 1H), 2.89-2.81 (m, 4H), 1.72 (s, 3H), 1.19 (t, 3H, J=7.5); lowresolution MS (ES⁺)m/e 594.96 (MH⁺).

Example 71(2S)-3-{4-[(5-ethyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenyl}-2-{[(Z)-3-oxo-3-phenyl-1-trifluoromethyl)-1-propenyl]amino}propanoicacid

The title compound was prepared (as described above for the preparationof Example 58) from 100 mg (0.27 mmol) of Intermediate 61, 91 mg (0.41mmol) of Intermediate 44, and 0.14 mL diisopropylethylamine in 2 mLMeOH. Attempted recrystallization from hot CH₃CN without success. Silicagel chromatography with MeOH/DCM (10%-20%) gave 91 mg (59% yield) ofExample 71: TLC (DCM/MeOH, 4/1): R_(f)=0.57; ¹H NMR (DMSO-d₆, 300 MHz)δ10.96 (br s, 1H), 7.94-7.89 (m, 4H), 7.58-7.44 (m, 6H), 7.12 (d, 2H,J=8.4), 6.89 (d, 2H, J=8.1), 6.16 (s, 1H), 4.93 (s, 2H), 4.20-4.11 (m,1H), 3.16-3.11 (m, 1H), 2.96-2.88 (m,1H), 2.77 (q, 2H, J=7.5), 1.17 (t,3H, J=7.5); low resolution MS (ES⁺)m/e 564.88 (MH⁺).

Example 72(2S)-3-(4-{[5-ethyl-2-(4-fluorophenyl)-1,3-oxazol-4-yl]methoxy}phenyl)-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoicacid

The title compound was prepared (as described above for the preparationof Example 58) from 700 mg (1.82 mmol) of Intermediate 63, 610 mg (2.73mmol) of Intermediate 44, and 0.95 mL diisopropylethylamine in 12 mLMeOH. Silica gel chromatography with MeOH/DCM (10%-20%) gave 580 mg (55%yield) of Example 72: TLC (DCM/MeOH, 4/1): R_(f)=0.50;¹H NMR (DMSO-d₆,300 MHz) δ10.95 (br s, 1H), 7.99-7.89 (m, 4H), 7.58-7.53 (m, 3H), 7.34(t, 2H, J=8.7), 7.12 (d, 2H, J=8.1), 6.89 (d, 2H, J=8.7), 6.16 (s, 1H),4.92 (s, 2H), 4.21-4.11 (m, 1H), 3.16-3.11 (m, 2H), 2.96-2.91 (m, 1H),2.79 (q, 2H, J=7.5), 1.17 (t, 3H, J=7.5); low resolution MS (ES⁺)m/e582.92 (MH⁺).

Example 73(2S)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-{4-[(5-ethyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenyl}propanoicacid

The title compound was prepared (as described above for the preparationof Example 2) from 100 mg (0.27 mmol) of Intermediate 61, 67 mg (0.27mmol) of Intermediate 25, and 0.08 mL triethylamine in MeOH (2.0 mL) andtrimethylorthoformate (0.5 mL) to yield 54 mg (51% yield) of Example 73after silica gel chromatography (5%-15% MeOH in DCM): TLC (DCM/MeOH,4/1): R_(f)=0.54; ¹H NMR (DMSO-d₆, 300 MHz) δ11.63 (d, 1H, J=9.3),7.98-7.90 (m, 4H), 7.73 (d, 2H, J=8.1), 7.50-7.48 (m, 3H), 7.16 (d, 2H,J=8.7), 6.90 (d, 2H, J=8.7), 5.6 (s, 1H), 4.93 (s, 2H), 4.24-4.18 (m,1H), 3.24-3.19 (m, 1H), 2.84-2.72 (m, 4H), 2.08-1.98 (m, 2H), 1.16 (t,3H, J=7.8), 0.91 (t, 3H, J=7.5); low resolution MS (ES⁺)m/e 593.10(MH⁺).

Example 74(2S)-3-(4-{[5-ethyl-2-(4-fluorophenyl)-1,3-oxazol-4-yl]methoxy}phenyl)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoicacid

The title compound was prepared (as described above for the preparationof Example 2) from 160 mg (0.42 mmol) of Intermediate 63, 102 mg (0.42mmol) of Intermediate 25, and 0.12 mL triethylamine in MeOH (3.0 mL) andtrimethylorthoformate (0.75 mL) to yield 117 mg (46% yield) of Example74 after silica gel chromatography (5%-15% MeOH in DCM): TLC (DCM/MeOH,4/1): R_(f)=0.57; ¹H NMR (DMSO-d₆, 300 MHz) δ11.63 (d, 1H, J=9.6),7.99-7.93 (m, 4H), 7.72 (d, 2H, J=8.1), 7.32 (t, 2H, J=8.7), 7.16 (d,2H, J=8.7), 6.90 (d, 2H, J=8.1), 5.6 (s, 1H), 4.91 (s, 2H), 4.26-4.20(m, 1H), 3.24-3.19 (m, 1H), 2.84-2.72 (m, 4H), 2.07-2.00 (m, 2H), 1.15(t, 3H, J=7.5), 0.91 (t, 3H, J=7.5); low resolution MS (ES⁺)m/e 611.10(MH⁺).

Example 75(2S)-3-{4-[(5-ethyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenyl}-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoicacid

The title compound was prepared (as described above for the preparationof Example 2) from 98 mg (0.27 mmol) of Intermediate 61, 62 mg (0.27mmol) of Intermediate 24, and 0.08 mL triethylamine in MeOH (2.0 mL) andtrimethylorthoformate (0.5 mL) to yield 95 mg (61% yield) of Example 75after silica gel chromatography (5%-15% MeOH in DCM): TLC (DCM/MeOH,4/1): R_(f)=0.59; ¹H NMR (DMSO-d₆, 300 MHz) δ11.55 (d, 1H, J=9.0),7.98-7.90 (m, 4H), 7.73 (d, 2H, J=8.4), 7.51-7.48 (m, 3H), 7.17 (d, 2H,J=8.4), 6.91 (d, 2H, J=8.4), 5.61 (s, 1H), 4.93 (s, 2H), 4.24-4.18 (m,1H), 3.23-3.16 (m, 1H), 2.86-2.73 (m, 4H), 1.72 (s, 3H), 1.17 (t, 3H,J=7.5); low resolution MS (ES⁺)m/e 579.05 (MH⁺).

Example 76(2S)-3-(4-{[5-ethyl-2-(4-fluorophenyl)-1,3-oxazol-4-yl]methoxy}phenyl)-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoicacid

The title compound was prepared (as described above for the preparationof Example 2) from 176 mg (0.46 mmol) of Intermediate 63, 105 mg (0.46mmol) of Intermediate 24, and 0.14 mL triethylamine in MeOH (3.0 mL) andtrimethylorthoformate (0.75 mL) to yield 152 mg (56% yield) of Example76 after silica gel chromatography (5%-15% MeOH in DCM): TLC (DCM/MeOH,4/1): R_(f)=0.55; ¹H NMR (DMSO-d₆, 300 MHz) δ11.55 (d, 1H, J=9.0),7.99-7.94 (m, 4H), 7.73 (d, 2H, J=8.4), 7.33 (t, 2H, J=8.7), 7.16 (d,2H), J=8.4), 6.90 (d, 2H, J=8.7), 5.61 (s, 1H), 4.93 (s, 2H), 4.23-4.18(m, 1H), 3.22-3.18 (m, ₁H), 2.85-2.73 (m, 4H), 1.72 (s, 3H), 1.17 (t,3H, J=7.5); low resolution MS (ES⁺)m/e 597.09 (MH⁺).

Example 77(2S)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-{4-[(5-ethyl-2-phenyl-1,3-thiazol-4-yl)methoxy]phenyl}propanoicacid

The title compound was prepared (as described above for the preparationof Example 2) from 1.44 g (2.90 mmol) of Intermediate 62, 710 mg (2.90mmol) of Intermediate 25, and 0.85 mL triethylamine in MeOH (20 mL) andtrimethylorthoformate (5 mL) to yield 985 mg (56% yield) of Example 77after silica gel chromatography (5%-15% MeOH in DCM): TLC (DCM/MeOH,4/1): R_(f)=0.45; ¹H NMR (DMSO-d₆, 300 MHz) δ11.65 (d, 1H, J=9.3), 7.97(d, 2H, J=8.1), 7.85 (m, 2H), 7.71 (d, 2H, J=8.1), 7.44 (m, 3H), 7.44(d, 2H, J=8.1), 7.16 (d, 2H, J=8.1), 5.61 (s, 1H), 5.05 (s, 2H),4.26-4.19 (m, 1H), 3.26-3.21 (m, 1H), 2.89-2.77 (m, 4H), 2.07-2.0 (m,2H), 1.19 (t, 3H, J=7.5), 0.91 (t, 3H, J=7.5); low resolution MS(ES⁺)m/e 609.07 (MH⁺).

Example 78(2S)-3-(4-{2-[5-ethyl-2-(4-fluorophenyl)-1,3-oxazol-4-yl]ethoxy}phenyl)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoicacid

The title compound was prepared (as described above for the preparationof Example 2) from 150 mg (0.29 mmol) of Intermediate 58 (TFA Salt), 108mg (0.3 mmol) of Intermediate 25, and 0.1 mL triethylamine in MeOH andtrimethylorthoformate to yield 70 mg (38% yield) of Example 78: TLC(DCM/MeOH, 90/10): R_(f)=0.26; ¹H NMR (DMSO-d₆, 300 MHz) δ11.62 (d, 1H,J=9.3), 7.99-7.93 (m, 4H), 7.74 (d, 2H, J=8.4), 7.32 (t, 2H, J=8.9),7.13 (d, 2H, J=8.4), 6.80 (d, 2H, J=8.5), 5.61 (s, 1H), 4.14 (m, 3H),3.4-3.1 (m, 2H, obscured by water peak), 2.88 (t, 2H, J=6.4), 2.70 (q,2H, J=7.4), 2.02 (m, 2H), 1.19 (t, 3H, J=7.5), 0.94 (t, 3H, J=7.5); lowresolution MS (ES⁺)m/e 625.2 (MH⁺).

Example 79(2S)-3-(4-{2-[5-ethyl-2-(4-fluorophenyl)-1,3-thiazol-4-yl]ethoxy}phenyl)-2-({(Z)-1-ethyl-3-oxo-3-[4-trifluoromethyl)phenyl]-1-propenyl}amino)propanoicacid

The title compound was prepared (as described above for the preparationof Example 2) from 150 mg (0.28 mmol) of Intermediate 56 (TFA Salt), 108mg (0.3 mmol) of Intermediate 25, and 0.1 mL triethylamine in MeOH andtrimethylorthoformate to yield 60 mg (33% yield) of Example 79: TLC(DCM/MeOH, 90/10): R_(f)=0.26; ¹H NMR (DMSO-d₆, 300 MHz) δ11.63 (d, 1H,J=9.4), 7.98 (d, 2H, J=8.0), 7.9-7.85 (m, 2H), 7.74 (d, 2H, J=8.3), 7.27(t, 2H, J=8.7), 7.13 (d, 2H, J=8.4), 6.80 (d, 2H, J=8.3), 5.62 (s, 1H),4.25 (m, 3H), 3.4-3.2 (m, 2H, obscured by water peak), 3.07 (t, 2H,J=6.3), 2.85-2.77 (m, 2H), 2.06-1.99 (m, 2H), 1.21 (t, 3H, J=7.4), 0.93(t, 3H, J=7.4); low resolution MS (ES⁺)m/e 641.12 (MH⁺).

Example 80(2S)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-{4-[2-(5-ethyl-2-phenyl-1,3-thiazol-4-yl)ethoxy]phenyl}propanoicacid

The title compound was prepared (as described above for the preparationof Example 2) from 150 mg (0.29 mmol) of Intermediate 57 (TFA Salt), 108mg (0.3 mmol) of Intermediate 25, and 0.1 mL triethylamine in MeOH andtrimethylorthoformate to yield 40 mg (22% yield) of Example 80: TLC(DCM/MeOH, 90/10): R_(f)=0.28; ¹H NMR (DMSO-d₆, 300 MHz ) δ11.62 (d, 1H,J=9.4), 7.98 (d, 2H, J=8.2), 7.85 (m, 2H), 7.74 (d, 2H, J=8.3),7.48-7.42 (m, 3H), 7.13 (d, 2H, J=8.4), 6.80 (d, 2H, J=8.3), 5.63 (s,1H), 4.23 (t, 2H, J=6.5), 4.2 (m, 1H), 3.2-3.05 (m, 3H), 2.89-2.75 (m,3H), 2.07-2.03 (m, 2H), 1.23 (t, 3H, J=7.5), 0.94 (t, 3H, J=7.5); lowresolution MS (ES⁺)m/e 622.91 (MH⁺).

The following Intermediates A-G were prepared to make radioligand forthe binding assay described below. Intermediate A:2-(4-(2-(Phenylmethyloxycarbonylamino)ethyl)phenoxy)-2-methylbutanoicacid

A solution of 4-(2-(phenylmethyloxycarbonylamino)ethyl)phenol (5.74 g;21.16 mmole) in 2-butanone (17 mL) and chloroform (6 g) was addeddropwise to a mixture of sodium hydroxide (9.0 g; 225 mmole) and2-butanone. (67 mL) whilst keeping the reaction temperature below 30° C.The mixture was allowed to stir at 30° C. for 4 h. Ether (100 mL) wasadded and the resultant solid was collected by filtration and washedwith ether (100 mL). The solid was dissolved in water (70 mL) and anyresidual ether removed by evaporation. 1N Hydrochloric acid was added toadjust the pH to 1, and the resulting oil was extracted withdichloroethane (3×50 mL). The combined extracts were dried (Na₂SO₄) andevaporated to afford a yellow oil (3.82 g; 49%). ¹H-NMR (CDCl₃) δ7.26(s, 5H), 7.09 (d, 2H, J=7.9 Hz), 6.88 (d, 2H, J=8.4 Hz), 5.09 (s, 2H),4.75 (br s, 1H), 3.42-3.44 (m, 2H), 2.75 (t, 2H, J=6.7 Hz), 1.92-2.00(m, 2H), 1.47 (s, 3H), 1.04 (t, 3H, J=2.6 Hz). Mass spectrometry ES⁻,m/e (M+H)⁺=372.

Intermediate B: Methyl2-(4-(2-(phenylmethyloxycarbonylamino)ethyl)phenoxy)-2-methyl butyrate

A solution of Intermediate A (2.0 g; 5.38 mmole) in dimethylformamide(12 mL) was treated with potassium carbonate (2.23 g; 16.14 mmole) andmethyl iodide (1.54 g; 10.76 mmole) and the resulting mixture stirred at23° C. for 2 h. The mixture was filtered and the solid collected waswashed with ethyl acetate (70 mL). The filtrate was washed with brine(4×50 mL), dried (Na₂SO₄) and evaporated. The residue was purified bychromatography on silica gel using hexane then 33% ethyl acetate-hexaneas eluent to afford a colorless oil (1.27 g; 61%). ¹H-NMR (DMSO-d₆)δ7.31 (m, 5H), 7.06 (d, 2H, J=8.4 Hz), 6.68 (d, 2H, J=8.4 Hz), 4.98 (s,2H), 3.67 (s, 3H), 3.15 (m, 2H), 2.62 (t, 2H, J=7.1 Hz), 1.86 (m, 2H),1.38 (s, 3H), 0.86 (t, 3H, J=7.3 Hz). Mass spectrometry ES⁺, m/e(M+Na)⁺=408.

Intermediate C: Methyl 2-4-(2-aminoethyl)phenoxy)-2-methyl butyrateacetate salt

A solution of Intermediate B (1.27 g; 3.29 mmole) in methanol (50 mL)and acetic acid (0.4 g) was treated with 10% palladium on carbon andshaken in a hydrogen atmosphere (50 psi) for 2 h. The catalyst wasfiltered through celite and the solvent was evaporated to afford ayellow oil in quantitative yield (1.04 g). ¹H-NMR (CDCl₃): δ7.06 (d, 2H,J=8.4 Hz), 6.77 (d, 2H, J=8.4 Hz), 6.70 (br s, 2H), 3.76 (s, 3H), 3.02(br s, 2H), 2.82 (m, 2H), 1.99 (s, 3H), 1.92 (m, 2H), 1.48 (s, 3H), 0.96(t, 3H , J=7.4 Hz). Mass spectrometry ES⁺, m/e (M+H)⁺=252.

Intermediate D: Methyl2-(4-(2-(2,4-dinitrophenylsulfonylamino)ethyl)phenoxy)-2-methyl butyrate

A solution of Intermediate C (2 g; 6.42 mmole) in CH₂Cl₂ (40 mL) wastreated with saturated sodium bicarbonate solution and the organic layerwas separated. The aqueous layer was extracted with CH₂Cl₂ (5×50 mL) andthe combined organic layers were dried (Na₂SO₄) and evaporated to affordthe free base as a yellow oil (1.61 g; 100%). This was dissolved inCH₂Cl₂ (40 mL) and treated with pyridine (0.45 g; 5.61 mmole) and2,4-dinitrophenylsulfonyl chloride (1.5 g; 5.61 mmole), and the mixturewas allowed to stir at 23° C. for 3 h. Water (60 mL) was added and theorganic layer separated, washed with water (3×40 mL) and saturatedsodium bicarbonate (40 mL). The organic layer was dried (Na₂SO₄) andevaporated and the residue purified by chromatography using 15-20%EtOAc-Hexane as eluent to afford a light yellow solid (1.38 g; 51%).¹H-NMR (CDCl₃): δ8.63 (d,1H, J=2.3 Hz), 8.49 (dd, 1H, J=8.4 Hz, J′=2.3Hz), 8.07 (d, 1H, J=8.4 Hz), 6.89 (d, 2H, J=8.4 Hz), 6.54 (d, 2H, J=8.4Hz), 5.34 (t, 1H, J=5.3 Hz), 3.78 (s, 3H), 3.48 (q, 2H, J=8.3 Hz), 2.75(t, 2H, J=6.6 Hz), 1.92 (m, 2H), 1.42 (s, 3H), 0.93 (t, 3H, J=7.5 Hz).

Intermediate E: Methyl2-(4-(2-((2,4-dinitrophenylsulfonyl)(hept-2-en-1-yl))amino)ethyl)phenoxy)-2-methylbutyrate

A solution of Intermediate D (315 mg; 0.654 mmole) in THF (15 mL) wastreated with triphenylphosphine (343 mg; 1.308 mmole), hept-2-en-1-ol(150 mg; 1.308 mmole) and diethylazodicarboxylate (228 mg; 1.308 mmole)and the mixture allowed to stir at 23° C. for 1 h. The solvent wasevaporated and the residue purified by chromatography using 10-15%EtOAc-Hexane as eluent to afford a semi-solid (400 mg; >100%). TLC andNMR shows that the desired compound is present along with1,2-(diethoxycarbonyl)hydrazine.

Intermediate F: Methyl2(4-(2-(hept-2-en-1-ylamino)ethyl)phenoxy)-2-methyl butanoate

A solution of Intermediate E (400 mg; 0.654 mmole) in CH₂Cl₂ (5 mL) wastreated with triethylamine (132 mg; 1.308 mmole) and mercaptoacetic acid(78 mg; 0.85 mmole) and the mixture was allowed to stir at 23° C. for 1h. The mixture was diluted with EtOAc (30 mL) and washed with water(3×20 mL) and aqueous sodium bicarbonate (30 mL). The organic layer wasdried (Na₂SO₄), evaporated and the residue purified by chromatographyusing 10% EtOAc-Hexane then 50% EtOAc-Hexane then MeOH as eluent toafford an oil (177 mg; 78% from intermediate 24). ¹H-NMR (CDCl₃): δ7.06(d, 2H, J=7.5 Hz), 6.75 (d, 2H, J=7.5 Hz), 5.59 (m, 2H), 3.76 (s, 3H),3.30 (d, 2H, J=6.3 Hz), 2.87 (m, 4H), 1.47 (s, 3H, 1.28 (m, 5H), 0.96(t, 3H, J=7.6 Hz), 0.86 (t, 3H, J=6.9 Hz).

Intermediate G: Methyl2-(4-(2-(1-hept-2-enyl-3-(2,4-difluorophenyl)ureido)ethyl)phenoxy)-2-methylbutyrate

A solution of Intermediate F (157 mg; 0.452 mmole) in methylene chloride(5 mL) was treated with 2,4-difluorophenylisocyanate (140 mg; 0.904mmole) and the mixture allowed to stand at 23° C. for 18 h. The solventwas evaporated and the residue purified by chromatography on silica gelusing 10% then 15% ethyl acetate-hexane as eluent to afford a yellowsemi-solid (212 mg; 93%). Contaminated with bis-(2,4-difluorophenyl)ureawhich co-elutes on column. ¹H-NMR (CDCl₃): δ8.85 (br s, 1H), 8.02 (m,1H), 7.09 (d, 2H, J=8.4 Hz), 6.77-6.90 (m, 4H), 5.70 (m, 1H), 5.36 (m,1H), 3.76 (s, 3H), 3.54 (t, 2H, J=7.3 Hz), 2.84 (t, 2H, J=7.1 Hz), 1.55(br s, 1H), 1.46 (s, 3H), 1.25-1.35 (m, 5H), 0.96 (t, 3H, J=7.3 Hz),0.88 (t, 3H, J=7.4 Hz). Mass spectrometry CI/AP⁺, m/e (M+H)⁺=503.

2-(4-(2-(1-Hept-2-enyl-3-(2,4-difluorophenyl)ureido)ethyl)phenoxy)-2-methylbutanoicacid (Radioligand Precursor)

A solution of Intermediate G (370 mg; 0.736 mmole) in methanol (15 mL)was treated with 1N NaOH (7.5 mL) and the mixture heated under refluxfor 2 h. The mixture was acidified with 1N HCl and extracted with ethylacetate (3×25 mL). The combined organic layers were washed with brine,dried (Na₂SO₄) and evaporated. The residue was purified bychromatography on silica gel using 20% ethyl acetate-hexane then ethylacetate as eluent to afford a tan oil (280 mg; 78%). ¹H-NMR (CDCl₃)δ7.95-8.09 (m,1H), 7.14 (d, 2H, J=7.1 Hz), 6.90 (d, 2H, J=7.4 Hz), 6.81(d, 2H, J=5.2 Hz), 5.66 (m, 1H), 5.37 (m,1H), 3.56 (t, 2H, J=7.4 Hz),2.87 (t, 2H, J=7.4 Hz), 2.00 (m, 4H), 1.44 (s, 3H), 1.27 (m, 6H), 1.03(t, 3H, J=7.3 Hz), 0.88 (t, 3H, J=7.3 Hz). Mass spectrometry ES⁻, m/e(M+H)⁺=489.

Radioligand:2-(4-(2-(2,3-Ditritio-1-heptyl-3-(2,4-difluorophenyl)ureido)ethyl)phenoxy)-2-methylbutanoicacid

A solution of radioligand precursor prepared above (10 mg) in anhydrousDMF (3.5 mL) was transferred to a reaction vessel containing 10% Pd/C(9.8 mg). The reaction vessel was evacuated and degassed via onefreeze-thaw-evacuation cycle and then exposed to tritium gas (10.1 Ci).After 4 h, the mixture was filtered through celite, evaporated and theresidue dissolved in acetonitrile. A portion of this solution (0.8 mL,26.6 mCi) was purified by HPLC (Dynamax C8, 25 min gradient from 4:1acetonitrile:0.1% TFA to 9:1 acetonitrile: 0.1% TFA, 235 nm). Fractionscontaing pure material were combined and evaporated under nitrogen. Theresidue was redissolved in acetonitrile to provide a solution of thetitle compound (82.0 Ci/mmol, radiochemical purity, 99%).

2-(4-(2-(1-Heptyl-3-(2,4-difluorophenyl)ureido)ethyl)phenoxy)-2-methylbutanoicacid

The unlabelled (“cold”) version of the above radioligand was prepared asa control. A solution of Intermediate G (10 mg) in anhydrous DMF (3.5mL) was transferred to a reaction vessel containing 10% Pd/C (9.8 mg).The reaction vessel was evacuated and degassed via onefreeze-thaw-evacuation cycle and then exposed to hydrogen gas. After 4h, the mixture was filtered through celite and evaporated. The residuewas purified by chromatography using 2% MeOH/CH₂Cl₂ as eluent to afforda gum (7 mg).

The radioligand prepared above was used in the PPARα binding assaydescribed below (in addition to ³H-BRL 49653 for the PPARγ bindingassay) to show that active compounds in the transfection assays werealso ligands for PPARα and PPARγ.

Binding Assay

Compounds were tested for their ability to bind to hPPARγ or hPPARαusing a Scintillation Proximity Assay (SPA). The PPAR ligand bindingdomain (LBD) was expressed in E. coli as polyHis tagged fusion proteinsand purified. The LBD was then labeled with biotin and immobilized onstreptavidin-modified scintillation proximity beads. The beads were thenincubated with a constant amount of the appropriate radioligand (³H-BRL49653 for PPARγ and2-(4-(2-(2,3-Ditritio-1-heptyl-3-(2,4-difluorophenyl)ureido)ethyl)phenoxy)-2-methylbutanoicacid for hPPARα) and variable concentrations of test compound, and afterequilibration the radioactivity bound to the beads was measured by ascintillation counter. The amount of nonspecific binding, as assessed bycontrol wells containing 50 μM of the corresponding unlabeled ligand,was subtracted from each data point. For each compound tested, plots ofligand concentration vs. CPM of radioligand bound were constructed andapparent K_(l) values were estimated from nonlinear least squares fit ofthe data assuming simple competitive binding. The details of this assayhave been reported elsewhere (see, Blanchard, S. G. et. al. Developmentof a Scintillation Proximity Assay for Peroxisome Proliferator-ActivatedReceptor gamma Ligand Binding Domain. Anal. Biochem. 1998, 257,112-119).

Preferably, the compounds of this invention bind to both hPPARγ andhPPARα. All of the above Examples 1-80 did bind to both hPPARγ andhPPARα. Apparent pK_(i) values were >6.3 for all Examples 1-80 in boththe PPARγ and PPARα binding assays described above (pK_(i)=-log of theconcentration of test compound required to achieve an apparent K_(i)value according to the equation K_(i)=IC₅₀/1+[L]/K_(d), where IC₅₀=theconcentration of test compound required to inhibit 50% of the specificbinding of the radioligand, [L] is the concentration of the radioligandused, and K_(d) is the dissociation constant for the radioligand at thereceptor).

Transfection Assay

Compounds were screened for functional potency in transient transfectionassays in CV-1 cells for their ability to activate the PPAR subtypes(transactivation assay). A previously established chimeric receptorsystem was utilized to allow comparison of the relative transcriptionalactivity of the receptor subtypes on the same target gene and to preventendogenous receptor activation from complicating the interpretation ofresults. See, for example, Lehmann, J. M.; Moore, L. B.; Simth-Oliver,T. A.; Wilkison, W. O.; Willson, T. M.; Kliewer, S. A., An antidiabeticthiazolidinedione is a high affinity ligand for peroxisomeproliferator-activated receptorγ (PPARγ), J. Biol. Chem., 1995, 270,12953-6. The ligand binding domains for murine and human PPARα, andPPARγ, were each fused to the yeast transcription factor GAL4 DNAbinding domain. CV-1 cells were transiently transfected with expressionvectors for the respective PPAR chimera along with a reporter constructcontaining five copies of the GAL4 DNA binding site driving expressionof secreted placental alkaline phosphatase (SPAP) and β-galactosidase.After 16 h, the medium was exchanged to DME medium supplemented with 10%delipidated fetal calf serum and the test compound at the appropriateconcentration. After an additional 24 h, cell extracts were prepared andassayed for alkaline phosphatase and β-galactosidase activity. Alkalinephosphatase activity was corrected for transfection efficiency using theβ-galactosidase activity as an internal standard (see, for example,Kliewer, S. A., et. al. Cell 83, 813-819 (1995)). Rosiglitazone (BRL49653) was used as a positive control in the hPPARγ assay. The positivecontrol in the hPPARα assay was2-[4-(2-(3-(4-fluorophenyl)-1-heptylureido)ethyl)-phenoxy]-2-methylpropionicacid, which can be prepared as described in Brown, Peter J., et. al.Synthesis Issue 7, 778-782 (1997), or patent publication WO 9736579.

All of the above Examples showed at least 50% activation of hPPARα andhPPARγ at concentrations of 10⁻⁷ M or less.

In vivo evaluation

Male Zucker Diabetic Fatty rats were lightly anesthetized withisofluorane gas and bleed by tail vein to obtain postprandial baselineconcentrations for plasma glucose, serum lipids and insulin. Animalswere baseline matched by plasma glucose and randomized into vehicle ortreatment groups with compound administration by oral gavage, b.i.d.,beginning at 8.5 weeks of age. Selected compounds were administered as asuspension in 0.5% methylcellulose for 7 consecutive days. Changes inbody weight and food consumption were monitored from representativeanimals from each group, over a 48 hr period. After 7 days of treatmentanimals were anesthetized, blood samples obtained and analyzed forplasma glucose and lactate, serum triglyceride, total and HDLcholesterol, non-esterified free fatty acids and insulin concentration.Livers were weighed and corrected for body weight. Values in Table 1 for% Glucose reduction represent a summary of the percent reduction fromvehicle control animals at day 7 relative to normalization defined inthis model as plasma glucose levels of 140 mg/dL.

TABLE 1 Biological activity Example % Glucose Reduction  1 39  7 34 1261 16 59 20 50 21 82 22 49 23 86 24 45 40 79 48 81

What is claimed is:
 1. A compound of formula (I), or a tautomeric form,pharmaceutically acceptable salt, or solvate thereof,

wherein; R¹ is hydrogen or C₁₋₃alkyl; R² is hydrogen, or C₁₋₈alkyloptionally substituted by one or more halogens; R³ is C₁₋₆alkyl,C₄₋₇cycloalkyl or cycloalkenyl, —OC₁₋₆alkyl, —NR′R′ (where each R′ isindependently hydrogen or C₁₋₃alkyl), a 5 or 6 membered heterocyclicgroup containing at least one oxygen, nitrogen, or sulfur ring atom(optionally substituted by one or more halogen, C₁₋₆alkyl optionallysubstituted by one or more halogens, —OC₁₋₆alkyl optionally substitutedby one or more halogens, —CN, or —NO₂), or phenyl (optionallysubstituted by one or more halogen, C₁₋₆alkyl optionally substituted byone or more halogens, —OC₁₋₆alkyl optionally substituted by one or morehalogens, —CN, or —NO₂); R⁴ is a 5 or 6 membered heterocyclic groupcontaining at least one oxygen, nitrogen, or sulfur ring atom(optionally substituted by one or more halogen, C₁₋₆alkyl optionallysubstituted by one or more halogens, —OC₁₋₆alkyl optionally substitutedby one or more halogens, —CN, or —NO₂), or phenyl (optionallysubstituted by one or more halogen, C₁₋₆alkyl optionally substituted byone or more halogens, —OC₁₋₆alkyl optionally substituted by one or morehalogens, —NR′R′, —CN, or —NO₂); R⁵ is hydrogen, halogen, or C₁₋₃alkyloptionally substituted by one or more halogens; R⁶ is hydrogen orC₁₋₃alkyl; X is O or S; and n is 1, 2, or
 3. 2. A compound of claim 1wherein R¹ is hydrogen or methyl.
 3. A compound of claim 1 wherein R² isC₁₋₈alkyl optionally substituted by one or more halogens.
 4. A compoundof claim 1 wherein R³ is, pyridine, pyrazine, thiophene, furan,thiazole, or phenyl (any of which may be optionally substituted by oneor more halogen, C₁₋₆alkyl optionally substituted by one or morehalogens, —OC₁₋₆alkyl optionally substituted by one or more halogens,—CN, or —NO₂) or C₄₋₇cycloalkyl.
 5. A compound of claim 4 wherein R³ isphenyl (optionally substituted by one or more halogen, C₁₋₆alkyloptionally substituted by one or more halogens, —OC₁₋₆alkyl optionallysubstituted by one or more halogens, —CN, or —NO₂).
 6. A compound ofclaim 1 wherein R⁴ is phenyl (optionally substituted by one or morehalogen, C₁₋₆alkyl optionally substituted by one or more halogens, or—OC₁₋₆alkyl optionally substituted by one or more halogens).
 7. Acompound of claim 1 wherein R⁵ is hydrogen, or C₁₋₃alkyl optionallysubstituted by one or more halogens.
 8. A pharmaceutical compositionaccording to claim 7 further comprising a pharmaceutically acceptablediluent or carrier.
 9. A compound of claim 1 wherein R⁶ is methyl orethyl.
 10. A compound of claim 1 selected from the group consisting of:(2S)-2-{[(Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid;(2S)-3-(4-{2-[2-(4-fluorophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoicacid;(2S)-3-(4-{2-[2-(4-isopropoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoicacid;(2S)-3-(4-{2-[2-(4-methoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoicacid;(2S)-2-{[(Z)-1-ethyl-3-oxo-3-phenyl-1-propenyl]amino}-3-[4-(2-{5-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}ethoxy)phenyl]propanoicacid;(2S)-2-{[(Z)-1-ethyl-3-(4-fluorophenyl)-3-oxo-1-propenyl]amino}-3-(4-{2-[2-(4-methoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)propanoicacid;(2S)-2-{[(Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]amino}-3-[4-(2-{5-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}ethoxy)phenyl]propanoicacid;(2S)-2-{[(Z)-1-ethyl-3-oxo-3-phenyl-1-propenyl]amino}-3-(4-{2-[2-(4-fluorophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)propanoicacid;(2S)-2-{[(Z)-1-ethyl-3-(4-fluorophenyl)-3-oxo-1-propenyl]amino}-3-(4-{2-[2-(4-fluorophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)propanoicacid;(2S)-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-{4-[2-(5-methyl-2-phenyl-1,3-thiazol-4-yl)ethoxy]phenyl}propanoicacid;(2S)-2-{[(Z)-3-(4-fluorophenyl)-1-methyl-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid;(2S)-2-{[(Z)-1-methyl-3-oxo-3-(2,3,4-trifluorophenyl)-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid;(2S)-2-{[(Z)-1-methyl-3-(4-nitrophenyl)-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid;(2S)-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid;(2S)-2-{[(Z)-1-ethyl-3-(4-fluorophenyl)-3-oxo-1-propenyl]amino}-3-(4-{2-[2-(4-isopropoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)propanoicacid;(2S)-2-{[(Z)-1-methyl-3-oxo-3-(2,4,5-trifluorophenyl)-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid;(2S)-2-{[(Z)-1-ethyl-3-oxo-3-phenyl-1-propenyl]amino}-3-(4-{2-[2-(4-isopropoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)propanoicacid;(2S)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid;(2S)-2-{[(Z)-1-methyl-3-(4-methylphenyl)-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid;(2S)-2-{[(Z)-1-ethyl-3-oxo-3-phenyl-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid;(2S)-3-(4-{2-[2-(4-fluorophenyl)-5-methyl-1,3-thiazol-4-yl]ethoxy}phenyl)-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoicacid;(2S)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-(4-{2-[2-(4-fluorophenyl)-5-methyl-1,3-thiazol-4-yl]ethoxy}phenyl)propanoicacid;(2S)-2-{[(Z)-1-butyl-3-oxo-3-phenyl-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid;(2S)-2-{[(Z)-3-(4-chlorophenyl)-1-methyl-3-oxo-1-propenyl]amino}-3-{4-[2(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid;(2S)-2-{[(Z)-1-methyl-3-(3-nitrophenyl)-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid;(2S)-2-({(Z)-3-[2-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-3-oxo-1-propenyl}amino)-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid;(2S)-2-{[(Z)-3-(4-isopropoxyphenyl)-1-methyl-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid;(2S)-2-{[(Z)-3-(2-chlorophenyl)-1-methyl-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid;(2S)-2-{[(Z)-3-(2-furyl)-1-methyl-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid;(2S)-2-{[(Z)-1-methyl-3-oxo-3-(2-pyrazinyl)-1-propenyl]amino}-3-{4-[2-(5-methyl-2phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid;(2S)-2-{[(Z)-3-(2,4-difluorophenyl)-1-methyl-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid;(2S)-2-{[(Z)-1-methyl-3-oxo-3-(1,3-thiazol-2-yl)-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid;(2S)-2-{[(Z)-1-methyl-3-oxo-3-(3-thienyl)-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid;(2S)-2-{[(Z)-1-methyl-3oxo-3-(2-pyridinyl)-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid;(2S)-2-{[(Z)-1-ethyl-3-(4-fluorophenyl)-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid;(2S)-2-{[(Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]amino3-{4-[2-(5-methyl-2-phenyl-1,3-thiazol-4-yl)ethoxy]phenyl}propanoicacid;(2S)-2-{[(Z)-3-(2-fluorophenyl)-1-methyl-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid;(2S)-2-{[(Z)-3-(2,3-difluorophenyl)-1-methyl-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid;(2S)-2-{[(Z)-3-(2-hydroxyphenyl)-1-methyl-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid;(2S)-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}-2-{[(Z)-3oxo-3-phenyl-1-propyl-1-propenyl]amino}propanoicacid;(2S)-2-{[(Z)-3-(4-methoxyphenyl)-1-methyl-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid;(2S)-3-(4-{2-[2-(4-methoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)-2-{[(Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]amino}propanoicacid;(2S)-2-{[(Z)-3-cyclohexyl-1-methyl-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid;(2S)-3-(4-{2-[2-(4-isopropoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)-2-{[(Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]amino}propanoicacid;(2S)-2-{[(Z)-1-heptyl-3-oxo-3-phenyl-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid;(2S)-2-{[(Z)-1-methyl-3-(3-methylphenyl)-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid;(2S)-2-{[(Z)-1-ethyl-3-oxo-3-phenyl-1-propenyl]amino}-3-(4-{2-[2-(4-methoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy]phenyl)propanoicacid;(2S)-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoicacid;(2S)-3-{4-[2-(5-methyl-2-phenyl-1,3-thiazol-4-yl)ethoxy]phenyl}-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoicacid;(2S)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-(4-{2-[2-(4-fluorophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)propanoicacid;(2S)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-(4-{2-[2-(4-isopropoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)propanoicacid;(2S)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-(4-{2-[2-(4-methoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)propanoicacid;(2S)-3-(4-{2-[2-(4-fluorophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoicacid;(2S)-2-{([(Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]amino}-3-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenyl}propanoicacid;(2S)-3-{4-[2-(5-ethyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}-2-{([(Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]amino}propanoicacid;(2S)-2-{[(Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]amino}-3-{4-[2-(2-phenyl-5-propyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid;(2S)-2-{[(Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]amino}-3-{4-[3-(5-methyl-2-phenyl-1,3-oxazol-4-yl)propoxy]phenyl}propanoicacid;(2S)-3-{4-[2-(5-ethyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoicacid;(2S)-3-{4-[3-(5-methyl-2-phenyl-1,3-oxazol-4-yl)propoxy]phenyl}-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoicacid;(2S)-3-{4-[2-(5-ethyl-2-phenyl-1,3-thiazol-4-yl)ethoxy]phenyl}-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoicacid;(2S)-3-(4-{2-[5-ethyl-2-(4-fluorophenyl)-1,3-oxazol-4-yl]ethoxy}phenyl)-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoicacid;(2S)-3-(4-{3-[5-ethyl-2-(4-fluorophenyl)-1,3-oxazol-4-yl]propoxy}phenyl)-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoicacid;(2S)-3-(4-{2-[5-ethyl-2-(4-fluorophenyl)-1,3-thiazol-4-yl]ethoxy}phenyl)-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoicacid;(2S)-3-(4-{3-[5-ethyl-2-(4-fluorophenyl)-1,3-oxazol-4-yl]propoxy}phenyl)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoicacid;(2S)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-{4[3-(5-ethyl-2-phenyl-1,3-oxazol-4-yl)propoxy]phenyl}propanoicacid;(2S)-3-(4-{3-[5-ethyl-2-(4-fluorophenyl)-1,3-oxazol-4-yl]propoxy}phenyl)-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoicacid;(2S)-3-{4-[3-(5-ethyl-2-phenyl-1,3-oxazol-4-yl)propoxy]phenyl}-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoicacid;(2S)-3-{4-[3-(5-ethyl-2-phenyl-1,3-oxazol-4-yl)propoxy]phenyl}-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoicacid;(2S)-3-{4-[(5-ethyl-2-phenyl-1,3-thiazol-4-yl)methoxy]phenyl}-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoicacid;(2S)-3-{4-[(5-ethyl-2-phenyl-1,3-thiazol-4-yl)methoxy]phenyl}-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoicacid;(2S)-3-{4-[(5-ethyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenyl}-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoicacid;(2S)-3-(4-{[(5-ethyl-2-(4-fluorophenyl)-1,3-oxazol-4-yl]methoxy{phenyl)-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoicacid;(2S)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-{4-[(5ethyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenyl}propanoicacid;(2S)-3-(4-{[5-ethyl-2-(4-fluorophenyl)-1,3-oxazol-4-yl]methoxy}phenyl)2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoicacid;(2S)-3-{4-[(5-ethyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenyl}-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoicacid;(2S)-3-(4-{[5-ethyl-2-(4-fluorophenyl)-1,3-oxazol-4-yl]methoxy}phenyl)-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoicacid;(2S)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-{4-[(5-ethyl-2-phenyl-1,3-thiazol-4-yl)methoxy]phenyl}propanoicacid;(2S)-3-(4-{2-[5-ethyl-2-(4-fluorophenyl)-1,3-oxazol-4-yl]ethoxy}phenyl)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoicacid;(2S)-3-(4-{2-[5-ethyl-2-(4-fluorophenyl)-1,3-thiazol-4-yl]ethoxy}phenyl)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoicacid;(2S)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-{4-[2-(5-ethyl-2-phenyl-1,3-thiazol-4-yl)ethoxy]phenyl}propanoicacid; and pharmaceutically acceptable salts and solvates thereof.
 11. Acompound of claim 1 selected from the group consisting of(2S)-2-{[(Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid;(2S)-2-{[(Z)-1-ethyl-3-oxo-3-phenyl-1-propenyl]amino}-3-[4-(2-{5-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}ethoxy)phenyl]propanoicacid;(2S)-2-{[(Z)-1-methyl-3-oxo-3-(2,3,4-trifluorophenyl)-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid;(2S)-2-{[(Z)-1-methyl-3-(4-nitrophenyl)-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid;(2S)-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid;(2S)-2-{[(Z)-1-methyl-3-oxo-3-(2,4,5-trifluorophenyl)-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid;(2S)-2-{[(Z)-1-ethyl-3-oxo-3-phenyl-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid;(2S)-3-(4-{2-[2-(4-fluorophenyl)-5-methyl-1,3-thiazol-4-yl]ethoxy}phenyl)-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoicacid;(2S)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-(4-{2-[2-(4-fluorophenyl)-5-methyl-1,3-thiazol-4-yl]ethoxy}phenyl)propanoicacid;(2S)-2-{[(Z)-1-butyl-3-oxo-3-phenyl-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid;(2S)-2-{[(Z)-3-(4-chlorophenyl)-1-methyl-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoicacid;(2S)-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}-2-{[(Z)-3-oxo-3-phenyl-1-propyl-1-propenyl]amino}propanoicacid;(2S)-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoicacid;(2S)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-(4-{2-[2-(4-fluorophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)propanoicacid;(2S)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-(4-{2-[2-(4-methoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)propanoicacid;(2S)-3-(4-{2-[2-(4-fluorophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoicacid;(2S)-2-{[(Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]amino}-3-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenyl}propanoicacid;(2S)-3-{4-[2-(5-ethyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}-2-{[(Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]amino}propanoicacid;(2S)-2-{[(Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]amino}-3-{4-[3-(5-methyl-2-phenyl-1,3-oxazol-4-yl)propoxy]phenyl}propanoicacid;(2S)-3-{4-[2-(5-ethyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoicacid;(2S)-3-{4-[2-(5-ethyl-2-phenyl-1,3-thiazol-4-yl)ethoxy]phenyl}-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoicacid;(2S)-3-(4-{2-[5-ethyl-2-(4-fluorophenyl)-1,3-oxazol-4-yl]ethoxy}phenyl)-2-{[(Z)-3-oxo-3phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoicacid;(2S)-3-(4-{3-[5-ethyl-2-(4-fluorophenyl)-1,3-oxazol-4-yl]propoxy}phenyl)-2{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoicacid;(2S)-3-(4-{2-[5-ethyl-2-(4-fluorophenyl)-1,3-thiazol-4-yl]ethoxy}phenyl)-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoicacid;(2S)-3-(4-{3-[5-ethyl-2-(4-fluorophenyl)-1,3-oxazol-4-yl]propoxy}phenyl)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoicacid;(2S)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-{4-[3-(5-ethyl-2-phenyl-1,3-oxazol-4-yl)propoxy]phenyl}propanoicacid;(2S)-3-(4-{3-[5-ethyl-2-(4-fluorophenyl)-1,3-oxazol-4-yl]propoxy}phenyl)-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoicacid;(2S)-3-{4-[3-(5-ethyl-2-phenyl-1,3-oxazol-4-yl)propoxy]phenyl}-2-({(Z)-1-methyl-3-oxy-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoicacid;(2S)-3-(4-{[5-ethyl-2-(4-fluorophenyl)-1,3-oxazol-4-yl]methoxy}phenyl)-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoicacid;(2S)-3-{4-[(5-ethyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenyl}-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoicacid;(2S)-3-(4-{[5-ethyl-2-(4-fluorophenyl)-1,3-oxazol-4-yl]methoxy}phenyl)-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoicacid;(2S)-3-(4-{2-[5-ethyl-2-(4-fluorophenyl)-1,3-thiazol-4-yl]ethoxy}phenyl)-2-({(Z)-1-ethyl-3-oxo-3-[4-trifluoromethyl)phenyl]-1propenyl}amino)propanoicacid; and pharmaceutically acceptable salts and soivates thereof.
 12. Acompound of claim 1 wherein said compound is a dual activator of hPPARγand hPPARα.
 13. A pharmaceutical composition comprising atherapeutically effective amount of a compound of claim
 1. 14. Apharmaceutical composition of claim 13 further comprising apharmaceutically acceptable diluent or carrier.